This application is a continuation of U.S. patent application Ser. No. 15/221,658 filed Jul. 28, 2016, which in turn claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 62/199,330 filed Jul. 31, 2015, and to U.S. Provisional Patent Application Ser. No. 62/335,290 filed May 12, 2016, the disclosure of each of the foregoing applications is hereby incorporated by reference in its entirety.

The present invention provides, in part, a novel compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

each of R1 and R2 is independently C1-6 alkyl that is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C1-4 alkoxy, C1-4 haloalkoxy, and C3-7 cycloalkyl, wherein the C3-7 cycloalkyl is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;

or R1 and R2, together with the N atom to which they are attached, form 4- to 14-membered heterocycloalkyl that is optionally substituted with R8 and optionally substituted with one or more independently selected R9 or R30;

each of R3 and R4 is independently H, halogen, OH, C1-6 alkyl, or C3-7 cycloalkyl, wherein the C1-6 alkyl of R3 and R4 is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C1-4 alkoxy, C1-4 haloalkoxy, and C3-6 cycloalkyl, and wherein the C3-7 cycloalkyl of R3 and R4 is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;

or R3 and R4, together with the C atom to which they are attached, form C3-7 cycloalkyl that is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;

each of R5 and R6 is independently H, C1-6 alkyl, or C3-7 cycloalkyl, wherein the C1-6 alkyl of R5 and R6 is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C1-4 alkoxy, C1-4 haloalkoxy, and C3-6 cycloalkyl, and wherein the C3-7 cycloalkyl of R5 and R6 is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;

or R5 and R6, together with the C atom to which they are attached, form C3-7 cycloalkyl that is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;

R7 is H, C1-6 alkyl, C3-7 cycloalkyl, or R10, wherein the C1-6 alkyl of R7 is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C1-4 alkoxy, C1-4 haloalkoxy, and C3-6 cycloalkyl, and wherein the C3-7 cycloalkyl of R7 is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;

or R7 and R6, together with the intervening moiety of “C(R5)—O” to which they are attached, form 4- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl that is optionally substituted with one or more substituents each independently selected from the group consisting of OH, oxo, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy, and wherein each of the ring-forming atoms of the 4- to 7-membered heterocycloalkyl is independently C, N, O, S, or P and wherein each of the ring-forming atoms of the 5- to 10-membered heteroaryl is C, N, O, or S;

or R7 and R3, together with the intervening moiety of “C(R4)—C(R5R6)—O” to which they are attached, form a 5- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl that is optionally substituted with one or more substituents each independently selected from the group consisting of OH, oxo, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy, and wherein each of the ring-forming atoms of the 5- to 7-membered heterocycloalkyl is independently C, N, O, S, or P, and wherein each of the ring-forming atoms of the 5- to 10-membered heteroaryl is C, N, O, or S;

R11 is 5- to 10-membered heteroaryl optionally substituted with one or more independently selected R31;

R12 is 4- to 14-membered heterocycloalkyl optionally substituted with one or more independently selected R32;

R13 is C6-10 aryl optionally substituted with one or more independently selected R33;

R14 is C3-14 cycloalkyl optionally substituted with one or more independently selected R34;

R15 is H, OH, halogen, C1-4 alkoxy, C1-4 alkyl, or cyclopropyl;

each of R21 and R22 is independently H, OH, halogen, C1-3 alkyl, or cyclopropyl, wherein the C1-3 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C1-3 alkoxy, C1-3 haloalkoxy, and cyclopropyl;

each of R81, R82, and R90 is independently selected from the group consisting of H, C1-6 alkyl, C3-7 cycloalkyl, and (C3-7 cycloalkyl)-C1-4 alkyl-, wherein each of the C1-6 alkyl, C3-7 cycloalkyl, and (C3-7 cycloalkyl)-C1-4 alkyl- is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, —OH, oxo, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl;

or OR81 and OR82, together with the P(═O) to which they are attached, form 4- to 10-membered heterocycloalkyl that is further optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, —OH, oxo, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl;

each of Cy1, Cy2, Cy3, and Cy4 is independently selected from the group consisting of R11, R12, R13, and R14;

each Rb is independently H or selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, C6-10 aryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-C1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (5- to 10-membered heteroaryl)-C1-4 alkyl-, wherein each of the selections from the group is optionally substituted with one or more substituents each independently selected from the group consisting of —OH, —CN, C1-4 alkyl, C3-7 cycloalkyl, C1-4 hydroxylalkyl, —S—C1-4 alkyl, —C(═O)H, —C(═O)—C1-4 alkyl, —C(═O)—O—C1-4 alkyl, —C(═O)—NH2, —C(═O)—N(C1-4 alkyl)2, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;

or Ra and Rb, together with the N atom to which they are attached, form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —OH, oxo, —C(═O)H, —C(═O)OH, —C(═O)—C1-4 alkyl, —C(═O)—NH2, —C(═O)—N(C1-4 alkyl)2, —CN, C1-4 alkyl, C3-6 cycloalkyl, (C3-6 cycloalkyl)-C1-2 alkyl-, C1-4 alkoxy, C1-4 hydroxylalkyl, C1-4 haloalkyl, and C1-4 haloalkoxy;

each Rc is independently selected from the group consisting of H, C1-4 alkyl, C3-7 cycloalkyl, and (C3-7 cycloalkyl)-C1-4 alkyl-;

each Rd is independently selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, a 4- to 14-membered heterocycloalkyl, C6-10 aryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-C1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (5- to 10-membered heteroaryl)-C1-4 alkyl-, wherein each of the selections from the group is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CF3, —CN, —OH, oxo, —S—C1-4 alkyl, C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;

each of f1 and f2 is independently 0, 1, or 2, provided that the sum of f1 and f2 is 1, 2, or 3;

m is 1, 2, or 3;

n is 1, 2, or 3;

p is 1, or 2; and

r is 0 or 1,

provided that when r is 1 and each of R3, R4, R5 and R6 is H, then the moiety of “—N(R1)(R2)” is other than optionally substituted 4-oxo-3H-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-yl.

In some embodiments, the compound of Formula I or pharmaceutically acceptable salt thereof is a compound of Formula I-1:

or pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I or pharmaceutically acceptable salt thereof is a compound of Formula I-a:

or pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I (or I-1 or I-a) or pharmaceutically acceptable salt thereof is a compound of Formula I-a1:

or pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I or pharmaceutically acceptable salt thereof is a compound of Formula I-b:

or pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I (or I-1 or I-b) or pharmaceutically acceptable salt thereof is a compound of Formula I-b1:

or pharmaceutically acceptable salt thereof.

Unless otherwise specified, the compound of Formula I or a salt thereof described in the following embodiments can be a compound of Formula I-1, I-a, I-a1, I-b, or I-b1, or a salt thereof.

In some embodiments, R1 and R2, together with the N atom to which they are attached, form 4- to 14-membered heterocycloalkyl that is optionally substituted with R8 and optionally substituted with one or more independently selected R9 or R30.

In some embodiments, R1 and R2, together with the N atom to which they are attached, form 4- to 14-membered heterocycloalkyl that is optionally substituted with R8 and optionally substituted with one or more independently selected R9.

In some embodiments, R1 and R2, together with the N atom to which they are attached, form 4- to 14-membered heterocycloalkyl that is substituted with R8 and optionally substituted with one or more independently selected R9.

In some embodiments:

the moiety of “—N(R1)(R2)” is a moiety of Formula a-1, a-2, a-3, a-4, a-5, or a-6:

ring A1 is 4- to 7-membered cycloalkyl or heterocycloalkyl;

t1 is 0, 1, 2, or 3;

t2 is 0, 1, 2, or 3;

t3 is 0, 1, 2, or 3;

s1 is 1 or 2; and

s2 is 1 or 2.

In some embodiments:

the moiety of Formula a-6 is a moiety of Formula a-6-1 or a-6-2:

X1 is O, NR41, or C(R42)2;

each of R41 and R42 is independently H or R9;

s3 is 0, 1, or 2, provided that when s3 is 0, then X1 is C(R42)2; and

s4 is 0, 1, or 2.

In some embodiments:

the moiety of “—N(R1)(R2)” is a moiety of Formula a-11, a-12, a-13, a-14, a-15, a-16-1, or a-16-2:

In some further embodiments, the moiety of Formula b-46-2a is a moiety of Formula b-46-2a-1, b-46-2a-2, or b-46-2a-3:

Rc is C1-3 alkyl or cyclopropyl;

t12 is 0, 1, or 2; and

each R30A is independently F, Cl, methyl, C1 fluoroalkyl, methoxy, or C1 fluoroalkoxy. In some further embodiments, Rc is C1-3 alkyl. In some yet further embodiments, Rc is methyl.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula b-46-2a-1; Rc is C1-3 alkyl; and each R30A is independently F, Cl, methyl, or C1 fluoroalkyl. In some further embodiments, Rc is methyl.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula b-46-2a-2; Rc is C1-3 alkyl; and each R30A is independently F, Cl, methyl, or C1 fluoroalkyl. In some further embodiments, Rc is methyl.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula b-46-2a-3.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula b-46-3.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula b-46-7. In some further embodiments, the moiety of Formula b-46-7 is a moiety of Formula b-46-7a or b-46-7a-1:

In some embodiments [e.g. wherein the moiety of “—N(R1)(R2)” is a moiety of Formula a-6, a-6-1, a-6-2, a-16-1, a-16-2, a-26, a-36, a-46-1, a-46-2, a-46-3, a-46-6, or a-46-7], t3 is 0 or 1; and t2 is 0 or 1. In some further embodiments, t3 is 0.

In some embodiments [e.g. wherein the moiety of “—N(R1)(R2)” is a moiety of Formula b-6, b-6-1, b-6-2, b-26, b-36, b-46-1, b-46-2, b-46-3, b-46-4, b-46-5, b-46-6, or b-47], t3 is 0 or 1; and t11 is 0, 1, or 2. In some further embodiments, t3 is 0 and t11 is 1 or 2. In yet further embodiments, t11 is 1.

In some embodiments [e.g. wherein the moiety of “—N(R1)(R2)” is a moiety of Formula b-46-1a-1, b-46-1a-2, b-46-2a-1, b-46-2a-2, b-46-2a-3, b-46-7a-1, or b-46-7a-2], t3 is 0 or 1; and t12 is 0 or 1. In some further embodiments, t3 is 0. In yet further embodiments, t12 is 0.

In some embodiments wherein the moiety of “—N(R1)(R2)” is a moiety of Formula b-46-1a-1, b-46-1a-2, b-46-2a-1, b-46-2a-2, b-46-2a-3, b-46-7a-1, or b-46-7a-2; each Rd is independently selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, a 4- to 7-membered heterocycloalkyl, C6-10 aryl, a 5- to 6-membered heteroaryl, (C3-7 cycloalkyl)-C1-4 alkyl-, (4- to 7-membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (5- to 6-membered heteroaryl)-C1-4 alkyl-, wherein each of the selections from the group is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CF3, —CN, —OH, oxo, —S—C1-4 alkyl, C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy.

In some embodiments, each of R3 and R4 is independently H, halogen, or methyl.

In some further embodiments, each of R3 and R4 is independently H or halogen (e.g., F).

In yet further embodiments, each of R3 and R4 is independently halogen (e.g., F).

In some other embodiments, each of R3 and R4 is independently H or methyl.

In some embodiments, each of R5 and R6 is independently H or C1-4 alkyl (e.g., methyl or ethyl). In some further embodiments, each of R5 and R6 is independently H or methyl.

In some embodiments, each of R5 and R6 is H.

In some embodiments, R7 is H or R10; and R10 is —P(═O)(OR81)(OR82).

In some embodiments, R7 is H.

In some embodiments, R7 is R10; and R10 is —P(═O)(OR81)(OR82).

In some embodiments, each of R81 and R82 is independently selected from the group consisting of H, C1-6 alkyl, and (C3-7 cycloalkyl)-C1-4 alkyl-, wherein each of the C1-6 alkyl and (C3-7 cycloalkyl)-C1-4 alkyl- is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, —OH, oxo, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, and C3-6 cycloalkyl. In some further embodiments, each R81 and R82 is independently H or C1-4 alkyl. In some yet further embodiments, each R81 and R82 is H.

In some embodiments:

the moiety of “—N(R1)(R2)” is a moiety of Formula a-1, a-2, a-3, a-11, a-12, a-13, a-16-2, a-46-2, or a-46-7;

each of R21 and R22 is independently H, OH, halogen, C1-3 alkyl, cyclopropylmethyl, or C1-3 haloalkyl;

R23 is H or C1-4 alkyl;

R11 is 5- to 6-membered heteroaryl optionally substituted with one or more independently selected R31;

R12 is 5- to 6-membered heterocycloalkyl optionally substituted with one or more independently selected R31;

R13 is phenyl optionally substituted with one or more independently selected R33; and

R14 is C3-8 cycloalkyl optionally substituted with one or more independently selected R34.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-12 or a-13; and R8 is -L1-R11 or -L3-R13. In some further embodiments, R8 is —R11.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-12 (or Formula a-12-1) wherein R8 is —R11 or —R13. In some further embodiments, R8 is —R11.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-13.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-13; and R8 is -L1-R11 or -L3-R13. In some further embodiments, R8 is —R11 or —R13. In yet further embodiments, R8 is —R11.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2, R8 is —NR23—S(═O)2—R, —NR23—S(═O)2—R12, —NR23—S(═O)2—R13, or —NR23—S(═O)2—R14; and R23 is C1-3 alkyl. In some further embodiments, R23 is methyl.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2; R8 is —NR23—C(═O)—R, —NR23—C(═O)—R12, —NR23—C(═O)—R13, or —NR23—C(═O)—R14; and R23 is C1-3 alkyl.

In some further embodiments, R23 is methyl.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2; and R8 is —R11, —R12, —R13, or —R14. In some further embodiments, R8 is —R11 or —R13. In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2; and R8 is -L1-R11 or -L3-R13. In some further embodiments, R8 is —NR23—S(═O)2—R11 or —NR23—S(═O)2—R13. In some yet further embodiments, R23 is H or C1-4 alkyl (e.g., methyl). In still further embodiments, R23 is C1-4 alkyl (e.g., methyl).

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2; and R8 is —O—R11 or —O—R13. In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2; and R8 is -L4-R14. In some further embodiments, R8 is —R14. In some embodiments:

the moiety of “—N(R1)(R2)” is a moiety of Formula a-14, a-15, a-16-1, a-36, a-46-1, a-46-3, a-46-4, a-46-5, or a-46-6;

R11 is 5- to 6-membered heteroaryl optionally substituted with one or more independently selected R31;

R12 is 5- to 6-membered heterocycloalkyl optionally substituted with one or more independently selected R31;

R13 is phenyl optionally substituted with one or more independently selected R33; and

R14 is C3-8 cycloalkyl optionally substituted with one or more independently selected R34. In some yet further embodiments, R23 is H or C1-4 alkyl (e.g., methyl).

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-14 or a-15; and R8 is -L1-R11 or -L3-R13.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-15; R8 is -L1-R11 or -L3-R13. In some further embodiments, each of L1 and L3 is independently absent, —(CR21R22)—, —S(═O)2—, —S(═O)2—NR23—, —S(═O)2—NR23—(CR21R22)—, —S(═O)2—(CR21R22)—, or —S(═O)2—(CR21R22)2—; and each of R21 and R22 is independently H, C1-3 alkyl, or cyclopropyl. In some yet further embodiments, each of L1 and L3 is independently —(CR21R22)— or —S(═O)2—.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-16-1, a-46-1, a-46-3, a-46-4, or a-46-6; and R8 is -L1-R11 or -L3-R13.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-1. In some further embodiments, R8 is -L1-R11, -L2-R12, -L3-R13, or -L4-R14; and each of each of L1, L2, L3, and L4 is —S(═O)2— or —C(═O)—. In some yet further embodiments, each of L1, L2, L3, and L4 is —S(═O)2—.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-1; and R8 is -L1-R11 or -L3-R13. In some further embodiments, each of L1 and L3 is independently absent, —(CR21R22)—, or —S(═O)2—. In some yet further embodiments, each of L1 and L3 is independently, —(CR21R22)—, or —S(═O)2—. In some still further embodiments, each of L1 and L3 is —S(═O)2—.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-1; R8 is -L1-R11; and L1 is absent, —(CR21R22)—, or —S(═O)2—. In some further embodiments, L1 is absent or —S(═O)2—. In some yet further embodiments, L1 is —S(═O)2—.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-1; R8 is -L3-R13; and L3 is absent, —(CR21R22)—, or —S(═O)2—. In some further embodiments, L3 is absent or —S(═O)2—. In some yet further embodiments, L3 is —S(═O)2—.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-1; R8 is -L1-R11 or -L3-R13; and each of L1 and L3 is —C(═O)— or —S(═O)2—. In some further embodiments, each of L1 and L3 is —S(═O)2—. In yet further embodiments, R8 is —S(═O)2—R13; R13 is phenyl optionally substituted with one or more independently selected R33. In still further embodiments, each R33 is independently selected from the group consisting of halogen (e.g. F or Cl), —CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2; and R8 is -L1-R11 or -L3-R13. In some further embodiments, each of L1 and L3 is independently absent, —O—, —NR23—, —S(═O)2—(CR21R22)— [for example, R8 is —(CR21R22)—S(═O)2—R11 or —(CR21R22)—S(═O)2—R13], —O—(CR21R22)— [for example, R8 is —O—(CR21R22)— —R11 or —O—(CR21R22)— —R13], —S(═O)2—NR23— [for example, R8 is —NR23—S(═O)2—R11 or —NR23—S(═O)2—R13], or —(CR21R22)—O—(CR21R22)—. In some yet further embodiments, R23 is H or C1-4 alkyl (e.g., methyl) and each of R21 and R22 is independently H, OH, halogen, C1-3 alkyl, cyclopropylmethyl, or C1-3 haloalkyl (for example, H, C1-3 alkyl, or cyclopropyl).

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2; and R8 is -L1-R11 or -L3-R13. In some further embodiments, each of L1 and L3 is independently —S(═O)2—NR23— [For example, R8 is —NR23—S(═O)2—R11 or —NR23—S(═O)2—R13]. In some yet further embodiments, R23 is H or C1-4 alkyl (e.g., methyl). In some still further embodiments, R23 is C1-4 alkyl (e.g., methyl).

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2; R8 is -L1-R11 or -L3-R13; and each of L1 and L3 is independently —NR23—. In some further embodiments, R23 is H or C1-4 alkyl (e.g., methyl).

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2; R8 is -L1-R11 or -L3-R13; and each of L1 and L3 is —O—.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2; R8 is -L4-R14; and L4 is —O—, —NR23—, —S(═O)2—(CR21R22)— [for example, R8 is —(CR21R22)—S(═O)2—R14], or —S(═O)2—NR23— [for example, R8 is —NR23—S(═O)2—R14]. In some further embodiments, L4 is —S(═O)2—NR23— [For example, R8 is —NR23—S(═O)2—R14]. In some yet further embodiments, R23 is H or C1-4 alkyl (e.g., methyl).

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2; R8 is —NR23—C(═O)—R, —NR23—C(═O)—R12, —NR23—C(═O)—R13, or —NR23—C(═O)—R14; and R23 is C1-3 alkyl or cyclopropropyl. In some further embodiments, R23 is C1-3 alkyl (e.g. methyl).

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2; and R8 is —R11 or —R13.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-4 or a-46-6; and R8 is -L1-R11 or -L3-R13. In some further embodiments, each of L1 and L3 is independently —(CR21R22)— or —S(═O)2—. In some yet further embodiments, each of L1 and L3 is —(CR21R22)—.

In some embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-6; and R8 is -L1-R11 or -L3-R13. In some further embodiments, each of L1 and L3 is independently —(CR21R22)— or —S(═O)2—. In some yet further embodiments, each of L1 and L3 is —(CR21R22)—; and each of R21 and R22 is independently H or C1-3 alkyl.

In some embodiments, the moiety of “—N(R1)(R2)” is a-46-7; R8 is -L1-R11, -L2-R12, -L3-R13, or -L4-R14; and each of L1, L2, L3, and L4 is —C(═O)— or —S(═O)2— [e.g. —C(═O)—]. In some further embodiments, R8 is -L1-R11 or -L3-R13; and each of L1 and L3 is —C(═O)—.

In some embodiments, each R9 is independently OH, oxo, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxylalkyl, C1-4 alkoxy, C1-4 haloalkoxy, or cyclopropyl. In some further embodiments, each R9 is independently OH, oxo, or methyl. In some yet further embodiments, each R9 is independently OH or methyl. In some still further embodiments, each R9 is OH.

In some embodiments of the compound of Formula I-a or a pharmaceutically acceptable salt thereof:

the moiety of “—N(R1)(R2)” is a moiety of Formula a-12 (or Formula a-12-1) wherein R8 is —R11 or —R13;

each of R5 and R6 is independently H or methyl;

R7 is H or —P(═O)(OR81)(OR82) [e.g., —P(═O)(OH)(OH)];

R11 is 5- to 6-membered heteroaryl optionally substituted with one or more independently selected R31;

R13 is phenyl optionally substituted with one or more independently selected R33;

each R36 is independently selected from the group consisting of halogen, —OH, C1-6 alkoxy, C1-6 haloalkoxy, —CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-7 cycloalkyl. In some further embodiments, each of R31 and R33 is independently selected from the group consisting of halogen, OH, C1-6 alkoxy, C1-6 haloalkoxy, —CN, C1-6 alkyl, C1-6 hydroxylalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C3-4 cycloalkyl. In some further embodiments, R8 is —R11.

In some embodiments of the compound of Formula I-a (including Formula I-a1) or a pharmaceutically acceptable salt thereof:

the moiety of “—N(R1)(R2)” is a moiety of Formula a-15 wherein R8 is -L1-R11 or -L3-R13;

each of L1 and L3 is independently absent, —(CR21R22)—, —S(═O)2—, —S(═O)2—NR23—, —S(═O)2—NR23—(CR21R22)—, —S(═O)2—(CR21R22)—, or —S(═O)2—(CR21R22)2— [e.g., each of L1 and L3 is independently —(CR21R22)— or —S(═O)2—)];

each of R21 and R22 is independently H, C1-3 alkyl, or cyclopropyl;

each of R5 and R6 is independently H or methyl;

R7 is H or —P(═O)(OR81)(OR82) [e.g., —P(═O)(OH)(OH)];

R11 is 5- to 6-membered heteroaryl optionally substituted with one or more independently selected R31;

R13 is phenyl optionally substituted with one or more independently selected R33;

each R36 is independently selected from the group consisting of halogen, —OH, C1-6 alkoxy, C1-6 haloalkoxy, —CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-7 cycloalkyl. In some further embodiments, each of R31 and R33 is independently selected from the group consisting of halogen, OH, C1-6 alkoxy, C1-6 haloalkoxy, —CN, C1-6 alkyl, C1-6 hydroxylalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C3-4 cycloalkyl. In some further embodiments, L1 is —S(═O)2—.

In some embodiments of the compound of Formula I-a (including Formula I-a1) or a pharmaceutically acceptable salt thereof:

the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-1 wherein R8 is -L3-R13;

each R36 is independently selected from the group consisting of halogen, —OH, C1-6 alkoxy, C1-6 haloalkoxy, —CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-7 cycloalkyl. In some further embodiments, R13 is phenyl optionally substituted with one or more substituents each independently selected from halogen, C1-4 alkoxy, C1-4 haloalkoxy, —CN, C1-4 alkyl, C1-4 haloalkyl, and C3-4 cycloalkyl.

In some embodiments of the compound of Formula I-a (including Formula I-a1) or a pharmaceutically acceptable salt thereof:

the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-1 wherein R8 is -L3-R13;

L3 is —S(═O)2—;

each of R5 and R6 is independently H or methyl;

R7 is H or —P(═O)(OR81)(OR82) [e.g., —P(═O)(OH)(OH)];

R13 is phenyl optionally substituted with one or more independently selected R33;

each R33 is independently selected from the group consisting of halogen, OH, C1-6 alkoxy, C1-6 haloalkoxy, —CN, C1-6 alkyl, C1-6 hydroxylalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C3-4 cycloalkyl. In some further embodiments, R13 is phenyl optionally substituted with one or more substituents each independently selected from halogen, C1-4 alkoxy, C1-4 haloalkoxy, —CN, C1-4 alkyl, C1-4 haloalkyl, and C3-4 cycloalkyl.

In some embodiments of the compound of Formula I-a (including Formula I-a1) or a pharmaceutically acceptable salt thereof:

the moiety of “—N(R1)(R2)” is a moiety of Formula b-26 (e.g. a moiety of Formula b-36);

each of R5 and R6 is independently H, methyl, or C1 fluoroalkyl (e.g. H or methyl); and

R7 is H or —P(═O)(OR81)(OR82) [e.g., —P(═O)(OH)(OH)]. In some further embodiments, each of R5 and R6 is independently H or methyl. In some yet further embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula b-36.

In some embodiments of the compound of Formula I-a (including Formula I-a1) or a pharmaceutically acceptable salt thereof:

the moiety of “—N(R1)(R2)” is a moiety of Formula b-46-1a (e.g. a moiety of Formula b-46-1a-1 or b-46-1a-2);

each of R5 and R6 is independently H, methyl, or C1 fluoroalkyl (e.g. H or methyl); and

R7 is H or —P(═O)(OR81)(OR82) [e.g., —P(═O)(OH)(OH)]. In some further embodiments, the moiety of “—N(R1)(R2)” is a moiety of Formula b-46-1a-1. In some yet further embodiments, each of R5 and R6 is independently H or methyl. In some embodiments of the compound of Formula I-a (including Formula I-a1) or a pharmaceutically acceptable salt thereof:

the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2 wherein R8 is -L1-R11 or -L3-R13;

each of L1 and L3 is independently absent, —O—, —NR23—, —S(═O)2—(CR21R22)— [for example, R8 is —(CR21R22)—S(═O)2—R11 or —(CR21R22)—S(═O)2—R13], or —S(═O)2—NR23— [for example, R8 is —NR23—S(═O)2—R11 or —NR23—S(═O)2—R13];

each R36 is independently selected from the group consisting of halogen, —OH, C1-6 alkoxy, C1-6 haloalkoxy, —CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-7 cycloalkyl. In some further embodiments, each of R31 and R33 is independently selected from the group consisting of halogen, OH, C1-6 alkoxy, C1-6 haloalkoxy, —CN, C1-6 alkyl, C1-6 hydroxylalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C3-4 cycloalkyl.

In some embodiments, the present invention provides a compound selected from Examples 1 to 150 (e.g. Examples 1 to 91) in the EXAMPLES section or a pharmaceutically acceptable salt thereof (or the parent compound thereof where the exemplary compound, for example, is a salt) herein below.

In some embodiments, the present invention provides a compound selected from:

The present invention includes any subset of any embodiment described herein.

The present invention includes combinations of two or more embodiments described hereinabove, or any subset thereof.

The present invention further provides the compound of Formula I or a pharmaceutically acceptable salt thereof (including all embodiments and combinations of two or more embodiments described herein or any subcombination thereof) for use in the treatment of a MAGL-mediated disease or disorder described herein.

The present invention further provides use of the compound of Formula I or a pharmaceutically acceptable salt thereof (including all embodiments and combinations of two or more embodiments described herein or any subcombination thereof) for treating a MAGL-mediated disease or disorder described herein.

The present invention further provides a method for treating a MAGL-mediated disease or disorder in a patient (e.g., a mammal such as a human) comprising administering to the patient a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof (including all embodiments and combinations of two or more embodiments described herein or any subcombination thereof).

The present invention further provides use of the compound of Formula I or a pharmaceutically acceptable salt thereof (including all embodiments and combinations of two or more embodiments described herein or any subcombination thereof) in the manufacture of a medicament for use in the treatment of a MAGL-mediated disease or disorder described herein.

The compound of Formula I or a pharmaceutically acceptable salt thereof of the present invention (or a metabolite thereof) is a MAGL inhibitor. Thus, the present invention further provides a method for inhibiting MAGL (i.e., an activity of MAGL either in vitro or in vivo), comprising contacting (including incubating) the MAGL with the compound of Formula I or a pharmaceutically acceptable salt thereof (such as one selected from Examples 1-91 herein) described herein.

The amount of the compound of Formula I or a pharmaceutically acceptable salt thereof used in any one of the methods (or uses) of the present invention is effective in inhibiting MAGL.

The term “therapeutically effective amount” as used herein refers to that amount of the compound (including a pharmaceutically acceptable salt thereof) being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of a MAGL-mediated disease or disorder (e.g., Alzheimer's disease, inflammation, or pain), a therapeutically effective amount refers to that amount which has the effect of relieving to some extent (or, for example, eliminating) one or more symptoms associated with the MAGL-mediated disease or disorder (e.g., psychotic symptom of Alzheimer's disease).

The term “treating”, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, unless otherwise indicated, refers to the act of treating as “treating” is defined herein. The term “treating” also includes adjuvant and neo-adjuvant treatment of a subject.

As used herein, the term “adjacent” in describing the relative positions of two substituent groups on a ring structure refers to two substituent groups that are respectively attached to two ring-forming atoms of the same ring, wherein the two ring-forming atoms are directly connected through a chemical bond. For example, in each of the following structures:

either of the two R700 groups is an adjacent group of R600.

As used herein, the term “n-membered”, where n is an integer, typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered heteroaryl group.

At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual sub-combination of the members of such groups and ranges.

For example, the term “C1-6 alkyl” is specifically intended to include C1 alkyl (methyl), C2 alkyl (ethyl), C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. For another example, the term “a 5- to 10-membered heteroaryl group” is specifically intended to include any 5-, 6-, 7-, 8-, 9- or 10-membered heteroaryl group.

As used herein, the term “alkyl” is defined to include saturated aliphatic hydrocarbons including straight chains and branched chains. In some embodiments, the alkyl group has 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. For example, the term “C1-6 alkyl,” as well as the alkyl moieties of other groups referred to herein (e.g., C1-6 alkoxy) refers to linear or branched radicals of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl). For yet another example, the term “C1-4 alkyl” refers to linear or branched aliphatic hydrocarbon chains of 1 to 4 carbon atoms; the term “C1-3 alkyl” refers to linear or branched aliphatic hydrocarbon chains of 1 to 3 carbon atoms; the term “C1-2 alkyl” refers to methyl and/or ethyl; and the term “C1 alkyl” refers to methyl. An alkyl group optionally can be substituted by one or more (e.g., 1 to 5) suitable substituents.

As used herein, the term “alkenyl” refers to aliphatic hydrocarbons having at least one carbon-carbon double bond, including straight chains and branched chains having at least one carbon-carbon double bond. In some embodiments, the alkenyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms.

For example, as used herein, the term “C2-6 alkenyl” means straight or branched chain unsaturated radicals (having at least one carbon-carbon double bond) of 2 to 6 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. An alkenyl group optionally can be substituted by one or more (e.g., 1 to 5) suitable substituents. When the compounds of Formula I contain an alkenyl group, the alkenyl group may exist as the pure E form, the pure Z form, or any mixture thereof.

As used herein, the term “alkynyl” refers to aliphatic hydrocarbons having at least one carbon-carbon triple bond, including straight chains and branched chains having at least one carbon-carbon triple bond. In some embodiments, the alkynyl group has 2 to 20, 2 to 10, 2 to 6, or 3 to 6 carbon atoms. For example, as used herein, the term “C2-6 alkynyl” refers to straight or branched hydrocarbon chain alkynyl radicals as defined above, having 2 to 6 carbon atoms. An alkynyl group optionally can be substituted by one or more (e.g., 1 to 5) suitable substituents.

As used herein, the term “cycloalkyl” refers to saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon rings (e.g., monocyclics such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclics including spiro, fused, or bridged systems (such as bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl or bicyclo[5.2.0]nonanyl, decahydronaphthalenyl, etc.). The cycloalkyl group has 3 to 15 carbon atoms. In some embodiments the cycloalkyl may optionally contain one, two or more non-cumulative non-aromatic double or triple bonds and/or one to three oxo groups. In some embodiments, the bicycloalkyl group has 6 to 14 carbon atoms. For example, the term “C3-14 cycloalkyl” refers to saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon rings of 3 to 14 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, or cyclodecanyl); and the term “C3-7 cycloalkyl” refers to saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon rings of 3 to 7 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentan-1-yl, or bicyclo[1.1.1]pentan-2-yl). For another example, the term “C3-6 cycloalkyl” refers to saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon rings of 3 to 6 ring-forming carbon atoms. For yet another example, the term “C3-4 cycloalkyl” refers to cyclopropyl or cyclobutyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings (including aryl and heteroaryl) fused to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclopentene, cyclohexane, and the like (e.g., 2,3-dihydro-1H-indene-1-yl, or 1H-inden-2(3H)-one-1-yl). The cycloalkyl group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents.

As used herein, the term “aryl” refers to all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated pi-electron system. The aryl group has 6 or 10 carbon atoms in the ring(s). Most commonly, the aryl group has 6 carbon atoms in the ring. For example, as used herein, the term “C6-10 aryl” means aromatic radicals containing from 6 to 10 carbon atoms such as phenyl or naphthyl. The aryl group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents.

As used herein, the term “heteroaryl” refers to monocyclic or fused-ring polycyclic aromatic heterocyclic groups with one or more heteroatom ring members (ring-forming atoms) each independently selected from O, S and N in at least one ring. The heteroaryl group has 5 to 14 ring-forming atoms, including 1 to 13 carbon atoms, and 1 to 8 heteroatoms selected from O, S, and N. In some embodiments, the heteroaryl group has 5 to 10 ring-forming atoms including one to four heteroatoms. The heteroaryl group can also contain one to three oxo or thiono (i.e., ═S) groups. In some embodiments, the heteroaryl group has 5 to 8 ring-forming atoms including one, two or three heteroatoms. For example, the term “5-membered heteroaryl” refers to a monocyclic heteroaryl group as defined above with 5 ring-forming atoms in the monocyclic heteroaryl ring; the term “6-membered heteroaryl” refers to a monocyclic heteroaryl group as defined above with 6 ring-forming atoms in the monocyclic heteroaryl ring; and the term “5- or 6-membered heteroaryl” refers to a monocyclic heteroaryl group as defined above with 5 or 6 ring-forming atoms in the monocyclic heteroaryl ring. For another example, term “5- or 10-membered heteroaryl” refers to a monocyclic or bicyclic heteroaryl group as defined above with 5, 6, 7, 8, 9 or 10 ring-forming atoms in the monocyclic or bicyclic heteroaryl ring. A heteroaryl group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents. Examples of monocyclic heteroaryls include those with 5 ring-forming atoms including one to three heteroatoms or those with 6 ring-forming atoms including one, two or three nitrogen heteroatoms. Examples of fused bicyclic heteroaryls include two fused 5- and/or 6-membered monocyclic rings including one to four heteroatoms.

As used herein, the term “heterocycloalkyl” refers to a monocyclic or polycyclic [including 2 or more rings that are fused together, including spiro, fused, or bridged systems, for example, a bicyclic ring system], saturated or unsaturated, non-aromatic 4- to 15-membered ring system (such as a 4- to 14-membered ring system, 4- to 12-membered ring system, 5- to 10-membered ring system, 4- to 7-membered ring system, 4- to 6-membered ring system, or 5- to 6-membered ring system), including 1 to 14 ring-forming carbon atoms and 1 to 10 ring-forming heteroatoms each independently selected from O, S and N (and optionally P or B when present). The heterocycloalkyl group can also optionally contain one or more oxo (i.e., ═O) or thiono (i.e., ═S) groups. For example, the term “4- to 12-membered heterocycloalkyl” refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 4- to 12-membered ring system that comprises one or more ring-forming heteroatoms each independently selected from O, S and N; and the term “4- to 10-membered heterocycloalkyl” refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 4- to 10-membered ring system that comprises one or more ring-forming heteroatoms each independently selected from O, S and N. For another example, the term “4- to 6-membered heterocycloalkyl” refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 4- to 6-membered ring system that comprises one or more ring-forming heteroatoms each independently selected from O, S and N; and the term “5- to 6-membered heterocycloalkyl” refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 5- to 6-membered ring system that comprises one or more ring-forming heteroatoms each independently selected from O, S and N. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings (including aryl and heteroaryl) fused to the nonaromatic heterocycloalkyl ring, for example pyridinyl, pyrimidinyl, thiophenyl, pyrazolyl, phthalimidyl, naphthalimidyl, and benzo derivatives of the nonaromatic heterocycloalkyl rings. The heterocycloalkyl group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents.

As used herein, the term “halo” or “halogen” group is defined to include fluorine, chlorine, bromine or iodine.

As used herein, the term “haloalkyl” refers to an alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom). For example, the term “C1-6 haloalkyl” refers to a C1-6 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom). For another example, the term “C1-4 haloalkyl” refers to a C1-4 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom); the term “C1-3 haloalkyl” refers to a C1-3 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom); and the term “C1-2 haloalkyl” refers to a C1-2 alkyl group (i.e., methyl or ethyl) having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom). For yet another example, the term “C1 haloalkyl” refers to a methyl group having one, two, or three halogen substituents. Examples of haloalkyl groups include CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl and the like.

As used herein, the term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. For example, the term “C1-6 alkoxy” or “C1-6 alkyloxy” refers to an —O—(C1-6 alkyl) group; and the term “C1-4 alkoxy” or “C1-4 alkyloxy” refers to an —O—(C1-4 alkyl) group; For another example, the term “C1-2 alkoxy” or “C1-2 alkyloxy” refers to an —O—(C1-2 alkyl) group. Examples of alkoxy include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. The alkoxy or alkyloxy group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents.

As used here, the term “haloalkoxy” refers to an —O-haloalkyl group. For example, the term “C1-6 haloalkoxy” refers to an —O—(C1-6 haloalkyl) group. For another example, the term “C1-4 haloalkoxy” refers to an —O—(C1-4 haloalkyl) group; and the term “C1-2 haloalkoxy” refers to an —O—(C1-2 haloalkyl) group. For yet another example, the term “C haloalkoxy” refers to a methoxy group having one, two, or three halogen substituents. An example of haloalkoxy is —OCF3 or —OCHF2.

As used herein, the term “fluoroalkyl” refers to an alkyl group having one or more fluorine substituents (up to perfluoroalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by fluorine). For example, the term “C1-2 fluoroalkyl” refers to a C1-2 alkyl group having one or more fluorine substituents (up to perfluoroalkyl, i.e., every hydrogen atom of the C1-2 alkyl group has been replaced by fluorine). For another example, the term “C1 fluoroalkyl” refers to a C1 alkyl group (i.e., methyl) having 1, 2, or 3 fluorine substituents). Examples of fluoroalkyl groups include CF3, C2F5, CH2CF3, CHF2, CH2F, and the like.

As used here, the term “fluoroalkoxy” refers to an —O-fluoroalkyl group. For example, the term “C1-2 fluoroalkoxy” refers to an —O—C1-2 fluoroalkyl group. For another example, the term “C1 fluoroalkoxy” refers to a methoxy group having one, two, or three fluorine substituents. An example of C1 fluoroalkoxy is —OCF3 or —OCHF2.

As used herein, the term “hydroxylalkyl” or “hydroxyalkyl” refers to an alkyl group having one or more (e.g., 1, 2, or 3) OH substituents. The term “C1-6 hydroxylalkyl” or “C1-6 hydroxyalkyl” refers to a C1-6 alkyl group having one or more (e.g., 1, 2, or 3) OH substituents. The term “C1-4 hydroxylalkyl” or “C1-4 hydroxyalkyl” refers to a C1-4 alkyl group having one or more (e.g., 1, 2, or 3) OH substituents; the term “C1-3 hydroxylalkyl” or “C1-3 hydroxyalkyl” refers to a C1-3 alkyl group having one or more (e.g., 1, 2, or 3) OH substituents; and the term “C1-2 hydroxylalkyl” or “C1-2 hydroxyalkyl” refers to a C1-2 alkyl group having one or more (e.g., 1, 2, or 3) OH substituents. An example of hydroxylalkyl is —CH2OH or —CH2CH2OH.

As used herein, the term “cyanoalkyl” refers to an alkyl group having one or more (e.g., 1, 2, or 3) —CN substituents. The term “C1-6 cyanoalkyl” refers to a C1-6 alkyl group having one or more (e.g., 1, 2, or 3) —CN substituents. For example, C1 cyanoalkyl is C1 alkyl (i.e., methyl) having one or more (e.g., one) —CN substituents. An example of cyanoalkyl is —CH2CN or —CH2CH2CN.

As used herein, the term “oxo” refers to ═O. When an oxo is substituted on a carbon atom, they together form a carbonyl moiety [—C(═O)—]. When an oxo is substituted on a sulfur atom, they together form a sulfinyl moiety [—S(═O)—]; when two oxo groups are substituted on a sulfur atom, they together form a sulfonyl moiety [—S(═O)2—].

As used herein, the term “thiono” refers to ═S. When an thiono is substituted on a carbon atom, they together form moiety of [—C(═S)—].

As used herein, the term “optionally substituted” means that substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties. A “substituted” atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a selection from the indicated substituent group (up to that every hydrogen atom on the designated atom or moiety is replaced with a selection from the indicated substituent group), provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group (i.e., CH3) is optionally substituted, then up to 3 hydrogen atoms on the carbon atom can be replaced with substituent groups.

As used herein, the term “optionally substituted C1-4 alkyl” refers to C1-4 alkyl optionally substituted by one or more (e.g., 1 to 5) substituents each independently selected from the group consisting of —OH, halogen, —CN, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, C1-4 alkoxy, and C1-4 haloalkoxy.

As used herein, the term “optionally substituted C3-6 cycloalkyl” refers to C3-6 cycloalkyl optionally substituted by one or more (e.g., 1 to 5) substituents each independently selected from the group consisting of —OH, halogen, —CN, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxylalkyl, C1-4 alkoxy, and C1-4 haloalkoxy.

As used herein, the term “optionally substituted C3-6 cycloalkyl-C1-2 alkyl-” refers to C3-6 cycloalkyl-C1-2 alkyl- optionally substituted by one or more (e.g., 1 to 5) substituents each independently selected from the group consisting of —OH, halogen, —CN, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxylalkyl, C1-4 alkoxy, and C1-4 haloalkoxy.

As used herein, the term “optionally substituted C1-4 alkoxy” refers to C1-4 alkoxy optionally substituted by one or more (e.g., 1 to 5) substituents each independently selected from the group consisting of —OH, halogen, —CN, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, C1-4 alkoxy, and C1-4 haloalkoxy.

As used herein, unless specified, the point of attachment of a substituent can be from any suitable position of the substituent. For example, piperidinyl can be piperidin-1-yl (attached through the N atom of the piperidinyl), piperidin-2-yl (attached through the C atom at the 2-position of the piperidinyl), piperidin-3-yl (attached through the C atom at the 3-position of the piperidinyl), or piperidin-4-yl (attached through the C atom at the 4-position of the piperidinyl). For another example, pyridinyl (or pyridyl) can be 2-pyridinyl (or pyridin-2-yl), 3-pyridinyl (or pyridin-3-yl), or 4-pyridinyl (or pyridin-4-yl).

As used herein, the point of attachment of a substituent can be specified to indicate the position where the substituent is attached to another moiety. For example, “—C1-2 alkyl-(C3-4 cycloalkyl)” means the point of attachment occurs at the “C1-2 alkyl” part of the “—C1-2 alkyl-(C3-4 cycloalkyl).” For another example, “(C3-4 cycloalkyl)-C1-2 alkyl-” also means the point of attachment occurs at the “C1-2 alkyl” part of the “(C3-4 cycloalkyl)-C1-2 alkyl-.”

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any of the ring-forming atoms in that ring that are substitutable (i.e., bonded to one or more hydrogen atoms), unless otherwise specified or otherwise implicit from the context. For example, as shown in the structure of Formula a-6 below, R8 may be bonded to any of the ring atoms of ring A1, but not to the ring including the N atom as shown in Formula a-6. For another example, as shown in Formula a-5 below (when t1 is 1), the R9 group can be bonded to any of the ring carbon atoms or the N atom (of the NH moiety) because the cross-bond is through both rings of the bicyclic structure; on the other hand, R8 can only be bonded to the N atom (of the NH moiety) and the two carbon ring atoms that are directly connected to the N atom (of the NH moiety). R8 cannot be bonded to either of the carbon atom of the moiety of “CH2CH2” (the H atoms are not shown) of the pyrrolidine ring of the bicyclic system of Formula a-5 because the bond does not cross the pyrrolidine ring.

As used herein, unless otherwise specifically indicated, a linkage/linker-a moiety that links two other moieties—can be attached to the other two moieties in either direction, if the linkage/linker is asymmetric. For example, when R8 is -L1-R11 and L1 is —S(═O)2—NR23—, then R8 can be either —S(═O)2—NR23—R11 or —NR23—S(═O)2—R1 (unless otherwise specifically indicated).

When a substituted or optionally substituted moiety is described without indicating the atom via which such moiety is bonded to a substituent, then the substituent may be bonded via any appropriate atom in such moiety. For example in a substituted arylalkyl, a substituent on the arylalkyl [e.g., (C6-10 aryl)-C1-4 alkyl-] can be bonded to any carbon atom on the alkyl part or on the aryl part of the arylalkyl. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As noted above, the compounds of Formula I may exist in the form of pharmaceutically acceptable salts such as acid addition salts and/or base addition salts of the compounds of Formula I. The phrase “pharmaceutically acceptable salt(s)”, as used herein, unless otherwise indicated, includes acid addition or base salts which may be present in the compounds of Formula I.

Pharmaceutically acceptable salts of the compounds of Formula I include the acid addition and base salts thereof.

Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

For a review on suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds of Formula I are known to one of skill in the art.

As used herein the terms “Formula I” or “Formula I or a pharmaceutically acceptable salt thereof” are defined to include all forms of the compound of Formula I or pharmaceutically salt thereof, including hydrates, solvates, isomers (including for example rotational stereoisomers), crystalline and non-crystalline forms, isomorphs, polymorphs, metabolites, and prodrugs thereof.

As is known to the person skilled in the art, amine compounds (i.e., those comprising one or more nitrogen atoms), for example tertiary amines, can form N-oxides (also known as amine oxides or amine N-oxides). An N-oxide has the formula of (R100)(R200)(R300)N+—O− wherein the parent amine (R100)(R200)(R300)N can be, for example, a tertiary amine (for example, each of R100, R200, R300 is independently alkyl, arylalkyl, aryl, heteroaryl, or the like), a heterocyclic or heteroaromatic amine [for example, (R100)(R200)(R300)N together forms 1-alkylpiperidine, 1-alkylpyrrolidine, 1-benzylpyrrolidine, or pyridine]. For instance, an imine nitrogen, especially a heterocyclic or heteroaromatic imine nitrogen, or pyridine-type nitrogen (

atom [such as a nitrogen atom in pyridine, pyridazine, or pyrazine], can be N-oxidized to form the N-oxide comprising the group

Thus, a compound according to the present invention comprising one or more nitrogen atoms (e.g., an imine nitrogen atom) may be capable of forming an N-oxide thereof (e.g., mono-N-oxides, bis-N-oxides or multi-N-oxides, or mixtures thereof depending on the number of nitrogen atoms suitable to form stable N-oxides).

As used herein, the term “N-oxide(s)” refer to all possible, and in particular all stable, N-oxide forms of the amine compounds (e.g., compounds comprising one or more imine nitrogen atoms) described herein, such as mono-N-oxides (including different isomers when more than one nitrogen atom of an amine compound can form a mono-N-oxide) or multi-N-oxides (e.g., bis-N-oxides), or mixtures thereof in any ratio.

Compounds of Formula I and their salts described herein further include N-oxides thereof.

In the description herein below, unless otherwise specified, compounds of Formula I (or compounds of the invention) include salts of the compounds and the N-oxides of the compounds or the salts.

As is also known to the person skilled in the art, tertiary amine compounds (i.e., those comprising one or more tertiary amine nitrogen atoms) can form quaternary ammonium salts. In the description herein below, unless otherwise specified, compounds of Formula I (or compounds of the invention) further include their quaternary ammonium salts.

Compounds of Formula I may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term ‘amorphous’ refers to a state in which the material lacks long-range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from apparent solid to a material with liquid properties occurs, which is characterised by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (‘melting point’).

Compounds of Formula I may exist in unsolvated and solvated forms. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

The compounds of Formula I may exist as clathrates or other complexes (e.g., co-crystals). Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the compounds of Formula I containing two or more organic and/or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. Co-crystals are typically defined as crystalline complexes of neutral molecular constituents that are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together; see O. Almarsson and M. J. Zaworotko, Chem. Commun. 2004, 17, 1889-1896. For a general review of multi-component complexes, see J. K. Haleblian, J. Pharm. Sci. 1975, 64, 1269-1288.

The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that have the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molecules which possess an ionic (such as —COO−Na+, —COO−K+, or —SO3−Na+) or non-ionic (such as —N−N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4th Edition (Edward Arnold, 1970).

The invention also relates to prodrugs of the compounds of Formula I. Thus certain derivatives of compounds of Formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of Formula I having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as “prodrugs”. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula I with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985), or in Prodrugs: Challenges and Reward, 2007 edition, edited by Valentino Stella, Ronald Borchardt, Michael Hageman, Reza Oliyai, Hans Maag, Jefferson Tilley, pages 134-175 (Springer, 2007).

Moreover, certain compounds of Formula I may themselves act as prodrugs of other compounds of Formula I.

Also included within the scope of the invention are metabolites of compounds of Formula I, that is, compounds formed in vivo upon administration of the drug.

The compounds of Formula I include all stereoisomers and tautomers. Stereoisomers of Formula I include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, atropisomers, and conformational isomers of the compounds of Formula I, including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs). Also included are acid addition or base addition salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

In some embodiments, the compounds of Formula I (including salts thereof) may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of Formula I may be depicted herein using a solid line (), a wavy line (), a solid wedge (), or a dotted wedge (). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. The use of a wavy line to depict bonds to asymmetric carbon atoms is meant to indicate that the stereochemistry is unknown (unless otherwise specified). It is possible that compounds of Formula I may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included. For example, unless stated otherwise, it is intended that the compounds of Formula I can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of Formula I and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.

In some embodiments, the compounds of Formula I may exist in and/or be isolated as atropisomers (e.g., one or more atropenantiomers). Those skilled in the art would recognize that atropisomerism may exist in a compound that has two or more aromatic rings (for example, two aromatic rings linked through a single bond). See e.g., Freedman, T. B. et al., Absolute Configuration Determination of Chiral Molecules in the Solution State Using Vibrational Circular Dichroism. Chirality 2003, 15, 743-758; and Bringmann, G. et al., Atroposelective Synthesis of Axially Chiral Biaryl Compounds. Angew. Chem., Int. Ed. 2005, 44, 5384-5427.

When any racemate crystallizes, crystals of different types are possible. One type is the racemic compound (true racemate) wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. Another type is a racemic mixture or conglomerate wherein two forms of crystal are produced in equal or different molar amounts each comprising a single enantiomer.

The compounds of Formula I may exhibit the phenomena of tautomerism and structural isomerism. For example, the compounds of Formula I may exist in several tautomeric forms, including the enol and imine form, the amide and imidic acid form, and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of Formula I. Tautomers may exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the compounds of Formula I. For example, when one of the following two tautomers (wherein R can be, for example, phenyl that is further substituted) is disclosed, those skilled in the art would readily recognize the other tautomer.

The present invention includes all pharmaceutically acceptable isotopically labelled compounds of Formula I or salts thereof wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulphur, such as 35S.

Certain isotopically labelled compounds of Formula I, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., 3H, and carbon-14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron-emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.

The present invention also provides compositions (e.g., pharmaceutical compositions) comprising a novel compound of Formula I. Accordingly, in one embodiment, the invention provides a pharmaceutical composition comprising (a therapeutically effective amount of) a novel compound of Formula I or a pharmaceutically acceptable salt thereof and optionally comprising a pharmaceutically acceptable carrier. In one further embodiment, the invention provides a pharmaceutical composition comprising (a therapeutically effective amount of) a compound of Formula I or a pharmaceutically acceptable salt thereof, optionally comprising a pharmaceutically acceptable carrier and, optionally, at least one additional medicinal or pharmaceutical agent (such as an antipsychotic agent or anti-schizophrenia agent described below). In one embodiment, the additional medicinal or pharmaceutical agent is an anti-schizophrenia agent as described below.

The pharmaceutically acceptable carrier may comprise any conventional pharmaceutical carrier or excipient. Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid, may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution or suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.

Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired.

The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. One of ordinary skill in the art would appreciate that the composition may be formulated in sub-therapeutic dosage such that multiple doses are envisioned.

In one embodiment the composition comprises a therapeutically effective amount of a compound of Formula I or salt thereof and a pharmaceutically acceptable carrier.

Compounds of Formula I (including salts thereof) are MAGL inhibitors. In some embodiments, the IC50 of a compound of Formula I (or its metabolite) is less than about 10 μM, 5 μM, 2 μM, 1 μM, 500 nM, 200 nM, 100 nM, 50, 40, 30, 20, 10, 5, 2, or 1 nM as determined by the method in Example AA described herein below.

In one embodiment of the present invention, the compounds of Formula I may be administered/effected by parenteral injection routes (e.g., intravenous injection route).

In one embodiment of the present invention, the compounds of Formula I may be administered/effected by oral routes.

Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the dosage unit forms of the invention are dictated by a variety of factors such as the unique characteristics of the therapeutic agent and the particular therapeutic or prophylactic effect to be achieved. In one embodiment of the present invention, the compounds of Formula I may be used to treat humans.

It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the present invention encompasses intra-patient dose-escalation as determined by the skilled artisan.

Determining appropriate dosages and regimens for administration of the chemotherapeutic agent is well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

The amount of the compound of Formula I administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, an effective dosage is in the range of about 0.0001 to about 50 mg per kg body weight per day, for example about 0.01 to about 10 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.007 mg to about 3500 mg/day, for example about 0.7 mg to about 700 mg/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.

As used herein, the term “combination therapy” refers to the administration of a compound of Formula I or a pharmaceutically acceptable salt thereof together with an at least one additional pharmaceutical or medicinal agent (e.g., an anti-schizophrenia agent), either sequentially or simultaneously.

The present invention includes the use of a combination of a compound of Formula I (including a salt thereof) and one or more additional pharmaceutically active agent(s). If a combination of active agents is administered, then they may be administered sequentially or simultaneously, in separate dosage forms or combined in a single dosage form. Accordingly, the present invention also includes pharmaceutical compositions comprising an amount of: (a) a first agent comprising a compound of Formula I (including a pharmaceutically acceptable salt thereof); (b) a second pharmaceutically active agent; and (c) a pharmaceutically acceptable carrier, vehicle or diluent.

Various pharmaceutically active agents may be selected for use in conjunction with the compounds of Formula I, depending on the disease, disorder, or condition to be treated. Pharmaceutically active agents that may be used in combination with the compositions of the present invention include, without limitation:

The compound of Formula I (including a salt thereof) is optionally used in combination with another active agent. Such an active agent may be, for example, an atypical antipsychotic or an anti-Parkinson's disease agent or an anti-Alzheimer's agent. Accordingly, another embodiment of the invention provides methods of treating a MAGL-mediated disease or disorder in a mammal, comprising administering to the mammal an effective amount of a compound of Formula I (including a pharmaceutically acceptable salt thereof) and further comprising administering another active agent.

As noted above, the compounds of Formula I or salts thereof may be used in combination with one or more additional anti-Alzheimer's agents which are described herein. When a combination therapy is used, the one or more additional anti-Alzheimer's agents may be administered sequentially or simultaneously with the compound of the invention. In one embodiment, the additional anti-Alzheimer's agent(s) is(are) administered to a mammal (e.g., a human) prior to administration of the compound of the invention. In another embodiment, the additional anti-Alzheimer's agent(s) is(are) administered to the mammal after administration of the compound of the invention. In another embodiment, the additional anti-Alzheimer's agent(s) is(are) administered to the mammal (e.g., a human) simultaneously with the administration of the compound of the invention (or a pharmaceutically acceptable salt thereof).

The invention also provides a pharmaceutical composition for the treatment of an inflammatory disorder (e.g., neuroinflammation) in a mammal, including a human, which comprises an amount of a compound of Formula I (including a salt thereof), as defined above (including hydrates, solvates and polymorphs of said compound or pharmaceutically acceptable salts thereof), in combination with one or more (for example one to three) anti-inflammation agents, wherein the amounts of the active agent and the combination when taken as a whole are therapeutically effective for treating the inflammatory disorder.

The invention also provides a pharmaceutical composition for treating a MAGL-mediated disease or disorder in a mammal, including a human, which comprises an amount of a compound of Formula I (including a salt thereof), as defined above (including hydrates, solvates and polymorphs of said compound or a salt thereof), in combination with one or more (for example one to three) other agents for treating the MAGL-mediated disease or disorder, wherein the amount of the active agents and the combination when taken as a whole are therapeutically effective for treating the MAGL-mediated disease or disorder.

It will be understood that the compounds of Formula I depicted above are not limited to a particular stereoisomer (e.g., enantiomer or diasteroisomer) shown, but also include all stereoisomers and mixtures thereof.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the invention, including salts of the compounds, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. The reactions for preparing compounds of the invention can be carried out in suitable solvents, which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

Compounds of Formula I and intermediates thereof may be prepared according to the following reaction schemes and accompanying discussion. Unless otherwise indicated, R1, R2, R3, R4, R5, R6, R7, r and structural Formula I (including I-a) in the reaction schemes and discussion that follow are as defined above. In general, the compounds of this invention may be made by processes which include processes analogous to those known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of this invention and intermediates thereof are provided as further features of the invention and are illustrated by the following reaction schemes. Other processes are described in the experimental section. The schemes and examples provided herein (including the corresponding description) are for illustration only, and not intended to limit the scope of the present invention.

Scheme 1 refers to the synthesis of compounds of Formula I. Referring to Scheme 1, a compound of Formula 1-3 [wherein Pg1 is an alcohol protecting group such as tert-butyldimethyl silyl (TBDMS) or p-methoxbenzyl] can be prepared by reacting an amine of Formula 1-1 with a compound of Formula 1-2 using standard methods of carbamate formation well known to those skilled in the art [for example, in the presence of phosgene, triphosgene, or a suitably activated carbonate reagent such as bis(pentafluorophenyl)carbonate or N,N′-disuccinimidyl carbonate]. Amines of Formula 1-1 may be obtained commercially, synthesized by methods described herein, or made by other methods well known to those skilled in the art. Carbamate formation may be accomplished in the presence of a base (such as triethylamine or hunigs base). A compound of Formula 1-4 may be obtained by deprotecting the compounds of Formula 1-3, using appropriate conditions depending on the selection of the Pg1 group. For example, where Pg1 is TBDMS, treatment with an acid such as trifluoroacetic acid in aprotic solvent such as dichloromethane may be employed. The compound of Formula 1-4 (which is a compound of Formula I wherein R7 is H) may optionally be converted to a compound of Formula I wherein R7 is other than H. For example, an alkylation reaction of the compound of Formula 1-4 with a halide compound (alkyl halide or cycloalkyl halide) can provide a compound of Formula I wherein R7 is C1-6 alkyl, C3-7 cycloalkyl. As another example, reaction of the alcohol of Formula 1-4 with diphosphoryl tetrachloride in a suitable solvent such as acetonitrile affords compounds of Formula I where R7 is —P(═O)(OH)2 or a salt thereof. For yet another example, reaction of the alcohol of Formula 1-4 with a sulfating agent [e.g. SO3, sulfamic acid H2N—S(═O)2(OH), chlorosulfonic acid HO—S(═O)2(Cl)] under suitable conditions can afford a compound of Formula I wherein R7 is —S(═O)2(OH) or a salt thereof.

Scheme 2 refers to synthesis of compounds of Formula I-a. An amine of Formula 1-1 may be reacted with a compound of Formula 2-2 [where Pg1 is a suitable alcohol protecting group, such as TBDMS or p-methoxybenzyl], using methods analogous to those described in Scheme 1, to form a carbamate of Formula 2-3. The compound of Formula 2-3 may be deprotected using appropriate conditions depending of the selection of Pg1 to give a compound of Formula 2-4. Similar to the discussions in Scheme 1, the compound of Formula 2-4 (which is a compound of Formula I-a wherein R7 is H) may optionally be converted to a compound of Formula I-a wherein R7 is other than H.

Scheme 3 refers to the preparation of compounds of Formula 3-4 [wherein Pg1 is an alcohol protecting group such TBDMS or p-methoxbenzyl], which can be used as a compound of Formula 1-2 in Scheme 1 [wherein r is 1; and both R5 and R6 are H]. Referring to Scheme 3, a compound of Formula 3-3 may be prepared by treatment of compound 3-1 with a base (such as n-butyllithium) followed by addition to formaldehyde 3-2 (or its equivalent such as paraformaldehyde) in the presence of a reducing agent such as sodium borohydride. Protection of the alcohol moiety in the compound of Formula 3-3 may be achieved by methods known to those skilled in the art. For example, where the Pg1 is TBDMS, the protection can be achieved by treatment of the compound of Formula 3-3 with an activated silyl reagent [such as tert-butyl(dimethyl)silyl chloride] in the presence of a base (such as 1H-imidazole) in a suitable non-protic solvent (such as THF or DMF) at a suitable temperature (e.g., ambient temperature).

Scheme 4 refers to a synthesis of compounds of Formula 4-3 [wherein Pg2 is an alcohol protecting group such p-methoxbenzyl], which can be used as a compound of Formula 1-2 in Scheme 1 [wherein r is 0]. Referring to Scheme 4, reaction of an epoxide of Formula 4-1 with an alcohol of Formula 4-2, in the presence of a base [e.g., NaN(TMS)2) in a in non-protic solvent (e.g., THF or DMF), affords a compound of Formula 4-3.

Scheme 4A refers to a synthesis of a compound of Formula 4A-5 or a salt thereof [i.e., a compound of Formula I-a or salt thereof, wherein R7 is —P(═O)(OH)2]. Referring to Scheme 4A, reaction of an epoxide of Formula 4A-1 with a phosphorus compound of Formula 4A-2 [wherein each of Pg2A is a hydroxyl protecting group such as benzyl], optionally in the presence of a base [e.g., NaN(TMS)2] in a in non-protic solvent (e.g., THF or DMF), affords a compound of Formula 4A-3. Similar to the carbamate formation reaction described in Schemes 1 and 2, reaction of the compound of Formula 4A-3 and an amine of Formula 1-1 affords a compound of Formula 4A-4. Depending on the choice of the Pg2A groups, removal of the protecting Pg2A groups under suitable conditions will afford a compound of Formula 4A-5 or a salt thereof.

Scheme 5 refers to the preparation of amines of Formula 5-8 (wherein R31 is aryl or heteroaryl that are optionally substituted), which can be used as a specific type of amine of Formula 1-1 for the preparation of compounds of Formula I or I-a in Schemes 1 and 2. The Weinreb amide of Formula 5-2 [where Pg3 is an amine protecting group such as tert-butoxycarbonyl (BOC)] can be prepared by coupling N-methoxymethanamine with a carboxylic acid of Formula 5-1 using a suitable coupling agent [e.g., O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU)]. Addition of a Grignard reagent (e.g., methylmagnesium bromide) to the Weinreb amide of Formula 5-2 results in a ketone of Formula 5-3. Treatment of the ketone of Formula 5-3 with N,N-dimethylformamide dimethyl acetal at elevated temperatures results in an enamine of Formula 5-4. Subsequent treatment with hydrazine (or its equivalent) in a protic solvent such as ethanol affords a pyrazole of Formula 5-5. A compound of Formula 5-7 can be obtained by reacting the pyrazole of Formula 5-5 with a (hetero)aryl boronic acid of Formula 5-6 in the presence of a catalyst (such as copper acetate) and a base (e.g., pyridine) in a suitable solvent (such as dichloromethane). Alternatively, the pyrazole of Formula 5-5 can be transformed into the compound of Formula 5-7 by palladium-catalyzed coupling with a suitable (hetero)aryl halide of Formula 5-9 wherein X is a suitable halide such are Cl, Br or I. Coupling can be achieved by reaction of the pyrazole of Formula 5-5 and (hetero)aryl halide of Formula 5-9 in the presence of a palladium catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [Pd(dppf)Cl2] together with a base such as potassium acetate at an elevated temperature in a non-protic solvent such as toluene. A compound of Formula 5-8 can be prepared by removal of the protecting group Pg3. For example, wherein the Pg3 is tert-butoxycarbonyl (BOC), cleavage can be achieved under acidic conditions by treatment with, for example, trifluoroacetic acid.

Scheme 6 refers to a synthesis of a spiromorpholine of Formula 6-6 (wherein Pg4 is a suitable amine protecting group such as BOC), which can be used as a starting material in Scheme 7. Referring to Scheme 6, reaction of a suitably protected piperidine of Formula 6-1 with nitromethane in the presence of a mild base such as triethylamine affords a compound of Formula 6-2. Reduction of the nitro moiety of the compound of Formula 6-2 to obtain an aminoalcohol of Formula 6-3 can be achieved by using methods such as palladium-catalyzed hydrogenation, for example utilizing 10% palladium on carbon in an alcoholic solvent under an atmosphere of hydrogen. Acetylation of the compound of Formula 6-3 can be achieved by treatment with chloroacetyl chloride in the presence of a suitable base such as potassium carbonate. Ring closure of the chloride compound of Formula 6-4 can be achieved by treatment with a suitable base (e.g., potassium tert-butoxide) in a non-protic solvent (e.g., THF) under reflux conditions to furnish a compound of Formula 6-5. A spiromorpholine compound of Formula 6-6 may be obtained by reduction of the amide functionality in the compound of Formula 6-5 using a suitable reducing agent (e.g., borane-dimethyl sulfide complex in THF).

Scheme 7 refers to the synthesis of compounds of Formula 7-4, 7-7, 7-10, or 7-13 from an amine of Formula 6-6. A compound of Formula 7-3 [wherein R70 can be, for example, R11, R12, R13, or R14] can be prepared by reacting the amine of Formula 6-6 with an aldehyde of Formula 7-2 using reductive amination conditions well known to those skilled in the art. For example, treatment with titanium(IV) isopropoxide and a reducing agent such as sodium borohydride can be employed. Reaction of an amine of Formula 6-6 with sulfonyl chlorides of Formula 7-5 [wherein R70 can be, for example, R11, R12, R13, or R14] in the presence of a suitable base (such as pyridine or sodium bicarbonate) results in a sulfonamide of Formula 7-6. An amine 6-6 can be treated with a suitably activated compound of Formula 7-8 (wherein Lg1 is a leaving group such as Cl) to give a compound of Formula 7-9 [wherein R71 can be, for example, R23; and R72 can be, for example, R11, R12, R13, R14, —(CR21R22)—R11, —(CR21R22)—R12, —(CR21R22)p-R13, or —(CR21R22)p—R14; or R71 and R72, together with the N atom to which they are attached, form 4- to 14-membered heterocycloalkyl optionally substituted with R8 and one or more independently selected R9]. A compound of Formula 7-12 [wherein R73 can be, for example, R11 or R12] can be prepared by metal-catalyzed coupling of compounds of Formula 6-6 with a compound of Formula 7-11 (wherein X is a halogen atom such as Cl or Br). A compound of Formula 7-3, 7-6, 7-9, or 7-12 can be converted to a compound of Formula 7-4, 7-7, 7-10, or 7-13, respectively, by appropriate deprotection. For example, when Pg4 is BOC, the deprotection can be achieved by treatment with an acid such as trifluoroacetic acid. A compound of Formula 7-4, 7-7, 7-10, or 7-13 can each be used as starting material [as a specific amine of Formula 1-1] for synthesis of compounds of Formula I (e.g., Formula I-a or I-b) as described in Schemes 1 and 2.

Scheme 8 refers to a synthesis of compounds of Formula 8-6 [where each t2a is independently 0 or 1; and R8A can be, for example, R11, R12, R3, or R14]. A compound of Formula 8-3 can be prepared by treatment of the aminoalcohol of Formula 8-1 (which can be prepared using the method as described in Scheme 6 for the aminoalcohol of Formula 6-3) with a sulfonyl chloride of Formula 8-2 in the presence of a suitable base (e.g., pyridine). Reaction of the compound of Formula 8-3 with a compound of Formula 8-4 (wherein each X is independently a suitable leaving group such as Br or Cl), in the presence of a base such as potassium carbonate in a polar aprotic solvent such as DMF, results in a compound of Formula 8-5. Removal of the protecting group results in a compound of Formula 8-6, which can be used as starting material [as a specific amine of Formula 1-1] in Schemes 1 and 2 for the preparation of compounds of Formula I (including compounds of Formula I-a or I-b).

Scheme 9 refers to a preparation of compounds of Formula 9-3 [where R8A can be, for example, R11, R12, R13, or R14]. A compound of formula 9-1 [where Pg4 is an amine protecting group (e.g., BOC)] can be obtained commercially or be readily synthesized by methods well known to those skilled in the art. A compound of Formula 9-2 can be obtained by reaction of a compound of Formula 9-1 with sulfonyl chlorides of Formula 8-2 in a suitable solvent (e.g., dichloromethane) in the presence of a suitable base (e.g., sodium bicarbonate). Deprotection of compounds of Formula 9-2 using appropriate conditions well known to those skilled in the art provides a compound of Formula 9-3. The compound of Formula 9-3 can be used as starting material [as a specific amine of Formula 1-1] in Schemes 1 and 2 for the preparation of compounds of Formula I (including compounds of Formula I-a or I-b).

Additional starting materials and intermediates useful for making the compounds of the present invention can be obtained from chemical vendors such as Sigma-Aldrich or can be made according to methods described in the chemical art.

Those skilled in the art can recognize that in all of the schemes described herein, if there are functional (reactive) groups present on a part of the compound structure such as a substituent group, for example R1, R2, R3, R4, R5, R6, R7, etc., further modification can be made if appropriate and/or desired, using methods well known to those skilled in the art. For example, a —CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to an amide; a carboxylic acid can be converted to an ester, which in turn can be reduced to an alcohol, which in turn can be further modified. For another example, an OH group can be converted into a better leaving group such as a methanesulfonate, which in turn is suitable for nucleophilic substitution, such as by a cyanide ion (CN−). For another example, an —S— can be oxidized to —S(═O)— and/or —S(═O)2—. For yet another example, an unsaturated bond such as C═C or C≡C can be reduced to a saturated bond by hydrogenation. One skilled in the art will recognize further such modifications. Thus, a compound of Formula I having a substituent that contains a functional group can be converted to another compound of Formula I having a different substituent group.

Similarly, those skilled in the art can also recognize that in all of the schemes described herein, if there are functional (reactive) groups present on a substituent group such as R1, R2, R3, R4, R5, R6, R7, etc., these functional groups can be protected/deprotected in the course of the synthetic scheme described here, if appropriate and/or desired. For example, an OH group can be protected by a benzyl, methyl, or acetyl group, which can be deprotected and converted back to the OH group in a later stage of the synthetic process. For another example, an NH2 group can be protected by a benzyloxycarbonyl (Cbz) or BOC group; conversion back to the NH2 group can be carried out at a later stage of the synthetic process via deprotection.

As used herein, the term “reacting” (or “reaction” or “reacted”) refers to the bringing together of designated chemical reactants such that a chemical transformation takes place generating a compound different from any initially introduced into the system. Reactions can take place in the presence or absence of solvent.

Compounds of Formula I may exist as stereoisomers, such as atropisomers, racemates, enantiomers, or diastereomers. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high-performance liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of Formula I (and chiral precursors thereof) may be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0% to 50% 2-propanol, typically from 2% to 20%, and from 0% to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g., Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety. Suitable stereoselective techniques are well known to those of ordinary skill in the art.

Where a compound of Formula I contains an alkenyl or alkenylene (alkylidene) group, geometric cis/trans (or Z/E) isomers are possible. Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Salts of the present invention can be prepared according to methods known to those of skill in the art.

The compounds of Formula I that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention can be prepared by treating the basic compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.

If the inventive compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, isonicotinic acid, lactic acid, pantothenic acid, bitartric acid, ascorbic acid, 2,5-dihydroxybenzoic acid, gluconic acid, saccharic acid, formic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and pamoic [i.e., 4,4′-methanediylbis(3-hydroxynaphthalene-2-carboxylic acid)] acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as ethanesulfonic acid, or the like.

Those compounds of Formula I that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts, and particularly the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of Formula I. These salts may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. These salts can also be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, for example under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are, for example, employed in order to ensure completeness of reaction and maximum yields of the desired final product.

Pharmaceutically acceptable salts of compounds of Formula I (including compounds of Formula I-a or I-b) may be prepared by, e.g., one or more of three methods:

(i) by reacting the compound of Formula I with the desired acid or base;

(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

(iii) by converting one salt of the compound of Formula I to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from completely ionized to almost non-ionized.

Polymorphs can be prepared according to techniques well-known to those skilled in the art, for example, by crystallization.

When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture may have almost identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art—see, for example, Stereochemistry of organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994).

The invention also includes isotopically labeled compounds of Formula I wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Isotopically labeled compounds of Formula I (or pharmaceutically acceptable salts thereof or N-oxides thereof) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula I with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

The compounds of Formula I should be assessed for their biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication.

Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of compounds of the present invention (or pharmaceutically acceptable salts thereof) and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

The compounds of the invention (including pharmaceutically acceptable salts thereof) may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the bloodstream directly from the mouth.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropyl methyl cellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described by Liang and Chen, Expert Opinion in Therapeutic Patents 2001, 11, 981-986.

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.

Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.

Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt-congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.

Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of Formula I, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.

The compound of Formula I (or pharmaceutically acceptable salts thereof or N-oxides thereof) may be water-soluble or insoluble. A water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a smaller proportion of the composition, typically up to 30 weight % of the solutes. Alternatively, the compound of Formula I may be in the form of multiparticulate beads.

The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.

Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.

Suitable modified release formulations for the purposes of the invention are described in U.S. Pat. No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

The compounds of the invention (including pharmaceutically acceptable salts thereof) may also be administered directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (for example to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of Formula I (including pharmaceutically acceptable salts thereof) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(DL-lactic-coglycolic acid) (PLGA) microspheres.

The compounds of the invention (including pharmaceutically acceptable salts thereof) can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone; as a mixture, for example, in a dry blend with lactose; or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurized container, pump, spray, atomizer (for example an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropyl methyl cellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as L-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 μL to 100 μL. A typical formulation may comprise a compound of Formula I or a pharmaceutically acceptable salt thereof, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or “puff” containing from 0.01 to 100 mg of the compound of Formula I. The overall daily dose will typically be in the range 1 μg to 200 mg, which may be administered in a single dose or, more usually, as divided doses throughout the day.

The compounds of the invention (including pharmaceutically acceptable salts thereof) may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

The compounds of the invention (including pharmaceutically acceptable salts thereof) may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, gels, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

The compounds of the invention (including pharmaceutically acceptable salts thereof) may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e., as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.

Since the present invention has an aspect that relates to the treatment of the disease/conditions described herein with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of Formula I, a prodrug thereof, or a salt of such compound or prodrug; and a second compound as described above. The kit comprises means for containing the separate compositions such as a container, a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are for example administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. In some embodiments, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen on which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, etc. . . . Second Week, Monday, Tuesday, . . . ” etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of Formula I compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.

In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. For example, the dispenser is equipped with a memory aid, so as to further facilitate compliance with the regimen. An example of such a memory aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.

The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters that can be changed or modified to yield essentially the same results. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art. In the following Examples and Preparations, “DMSO” means dimethyl sulfoxide, “N” where referring to concentration means Normal, “M” means molar, “mL” means milliliter, “mmol” means millimoles, “μmol” means micromoles, “eq.” means equivalent, “° C.” means degrees Celsius, “MHz” means megahertz, “HPLC” means high-performance liquid chromatography.

EXAMPLES

The following illustrate the synthesis of various compounds of the present invention. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art.

Experiments were generally carried out under inert atmosphere (nitrogen or argon), particularly in cases where oxygen- or moisture-sensitive reagents or intermediates were employed. Commercial solvents and reagents were generally used without further purification.

Anhydrous solvents were employed where appropriate, generally AcroSeal® products from Acros organics or DriSolv® products from EMD Chemicals. In other cases, commercial solvents were passed through columns packed with 4 Å molecular sieves, until the following QC standards for water were attained: a) <100 ppm for dichloromethane, toluene, N,N-dimethylformamide and tetrahydrofuran; b) <180 ppm for methanol, ethanol, 1,4-dioxane and diisopropylamine. For very sensitive reactions, solvents were further treated with metallic sodium, calcium hydride or molecular sieves, and distilled just prior to use. Products were generally dried under vacuum before being carried on to further reactions or submitted for biological testing. Mass spectrometry data is reported from either liquid chromatography-mass spectrometry (LCMS), atmospheric pressure chemical ionization (APCI) or gas chromatography-mass spectrometry (GCMS) instrumentation. Chemical shifts for nuclear magnetic resonance (NMR) data are expressed in parts per million (ppm, 6) referenced to residual peaks from the deuterated solvents employed. In some examples, chiral separations were carried out to separate enantiomers or diastereomers of certain compounds of the invention (in some examples, the separated enantiomers are designated as ENT-1 and ENT-2, or the separated diastereomers are designated as DIAST-1 and DIAST-2, according to their order of elution). In some examples, the optical rotation of an enantiomer was measured using a polarimeter. According to its observed rotation data (or its specific rotation data), an enantiomer with a clockwise rotation was designated as the (+)-enantiomer and an enantiomer with a counter-clockwise rotation was designated as the (−)-enantiomer. Racemic compounds are indicated by the presence of (+/−) adjacent to the structure; in these cases, indicated stereochemistry represents the relative (rather than absolute) configuration of the compound's substituents.

Reactions proceeding through detectable intermediates were generally followed by LCMS, and allowed to proceed to full conversion prior to addition of subsequent reagents. For syntheses referencing procedures in other Examples or Methods, reaction conditions (reaction time and temperature) may vary. In general, reactions were followed by thin-layer chromatography or mass spectrometry, and subjected to work-up when appropriate.

Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluents/gradients were chosen to provide appropriate Rfs or retention times.

For clarity purposes, the stereochemistry of the substituents on the 3-azabicyclo[3.1.0]hexyl skeleton in Examples and intermediates herein is indicated by using Chemical Abstracts nomenclature. The stereochemistry of the other compounds in the Examples and intermediates herein is indicated by using IUPAC nomenclature.

Bis(pentafluorophenyl) carbonate (1.33 g, 3.37 mmol) was added to a 0° C. solution of C1 (929 mg, 3.71 mmol) in acetonitrile (30 mL). Triethylamine (1.71 g, 16.9 mmol) was added in a drop-wise manner, and the reaction was warmed to 25° C. and stirred for 2 hours. The resulting solution of C2 was used directly in Step 11. For subsequent syntheses described herein that utilize C2, this material was generated at the appropriate scale, and the reaction solution of C2 was used directly in the coupling reaction.

A solution of C9 (742 mg, 2.17 mmol) in dichloromethane (5 mL) was cooled in an ice bath, and then treated with trifluoroacetic acid (3 mL). The reaction mixture was stirred for 30 minutes at 25° C., whereupon it was concentrated in vacuo, affording the product (1.27 g) as a yellow gum. LCMS m/z 243.0 [M+H]+.

To a solution of C1 (701 mg, 2.80 mmol) in dichloromethane (20 mL) were added triethylamine (850 mg, 8.40 mmol) and 1,1′-[carbonylbis(oxy)]dipyrrolidine-2,5-dione (717 mg, 2.80 mmol). The reaction mixture was stirred for 18 hours at 25° C., then used directly in Step 4. For subsequent syntheses described herein that utilize C17, this material was generated at the appropriate scale, and the reaction solution of C17 was used directly in the coupling reaction.

A mixture of C18 (1.0 g, 2.9 mmol) in trifluoroacetic acid (10 mL) was stirred for 30 minutes at 15° C., whereupon it was concentrated in vacuo. The residue was triturated with tert-butyl methyl ether (10 mL) to provide the product as a white solid, which was used directly in the following step. LCMS m/z 243.9 [M+H]+.

Triethylamine (9.28 g, 91.7 mmol) was added to a 0° C. solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (4.70 g, 18.3 mmol) in acetonitrile (60 mL); C2 (reaction solution in acetonitrile, containing 27.5 mmol) was then added drop-wise, and the reaction mixture was stirred at 0° C. few minutes. It was then allowed to warm to 25° C. and stir for 15 hours, whereupon it was concentrated in vacuo and purified via silica gel chromatography (Gradient: 0% to 100% dichloromethane in petroleum ether). The product (11.2 g) was isolated as a yellow oil, which by LCMS analysis was impure; this material was used without additional purification. LCMS m/z 555.1 [M+Na+].

The absolute configurations indicated for 8 and 9 were established by relation to the X-ray crystal structure determination of C48 (see Example 15) in the following manner: C48 and its enantiomer C49 were converted to samples of the general structure of 8 and 9 using the methods described in this Example. Supercritical fluid chromatography (Column: Chiral Technologies Chiralpak AD, 5 um; Mobile phase A: carbon dioxide; Mobile phase B: 2-propanol; Gradient: 5% to 60% B) provided a clear correlation between the material derived from C48 and 9 (retention times 7.44 and 7.45 minutes). Likewise, the material derived from C49 exhibited a very similar retention time to that of 8 (6.86 and 6.87 minutes).

Conversion of C31 to the product was carried out using the method described for synthesis of C32 from C31 in Example 7, providing C38 as a colorless gum. Yield: 130 mg, 0.220 mmol, 79%. LCMS m/z 612.9 [M+Na+].

Trifluoroacetic acid (3 mL) was added to a solution of C39 (235 mg, 0.605 mmol) in dichloromethane (5 mL) and the reaction mixture was stirred for 30 minutes at room temperature. After removal of solvents in vacuo, the residue was taken up in aqueous sodium bicarbonate solution (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product as a gum. Yield: 116 mg, 0.402 mmol, 66%. LCMS m/z 289.1 [M+H]+.

To a solution of C41 (60.0 mg, 0.134 mmol) in tetrahydrofuran (10 mL) was added 10% palladium on carbon (14.3 mg, 13.4 μmol), and the mixture was stirred under a hydrogen atmosphere (45 psi) for 18 hours at 50° C. After filtration of the reaction mixture, the filter cake was washed with methanol (20 mL); the combined filtrates were concentrated in vacuo to afford the product as a colorless gum. Yield: 42.0 mg, 0.134 mmol, 100%. LCMS m/z 312.9 [M+H]+.

Conversion of C42 to the product was effected using the method described for synthesis of C30 in Example 7. In this case, purification was carried out via preparative thin layer chromatography on silica gel (Eluent: 3:1 petroleum ether/ethyl acetate) to afford the product as a gum. Yield: 55 mg, 93 μmol, 35%. LCMS m/z 611.0 [M+Na+].

The absolute configurations shown were established as follows: a portion of this batch of C48 was recrystallized from dichloromethane/tert-butyl methyl ether, and its absolute configuration was determined via single crystal X-ray structure determination:

Single-Crystal X-Ray Structural Determination of C48

Data collection was performed on a Bruker APEX diffractometer at room temperature. Data collection consisted of omega and phi scans.

The structure was solved by direct methods using SHELX software suite in the space group P212121. The structure was subsequently refined by the full-matrix least squares method. All non-hydrogen atoms were found and refined using anisotropic displacement parameters.

The hydrogen atom located on nitrogen was found from the Fourier difference map and refined with distances restrained. The remaining hydrogen atoms were placed in calculated positions and were allowed to ride on their carrier atoms. The final refinement included isotropic displacement parameters for all hydrogen atoms.

Analysis of the absolute structure using likelihood methods (Hooft, 2008) was performed using PLATON (Spek, 2010). The results indicate that the absolute structure has been correctly assigned. The method calculates that the probability that the structure is correct is 100.0. The Hooft parameter is reported as 0.015 with an esd of 0.09.

The final R-index was 4.2%. A final difference Fourier revealed no missing or misplaced electron density.

Conversion of C52 to C53 was carried out using the method described for synthesis of C34 from C33 in Examples 8 and 9. Purification in this case was effected via preparative thin layer chromatography on silica gel (Eluent: 1:1 ethyl acetate/petroleum ether) to afford the product as a colorless gum. Yield: 60 mg, 0.11 mmol, 58% over 3 steps. LCMS m/z 569.1 [M+Na+].

Bis(pentafluorophenyl) carbonate (158 mg, 0.401 mmol) was added to a 0° C. solution of C59 (118 mg, 0.401 mmol) in acetonitrile (4 mL). Triethylamine (122 mg, 1.20 mmol) was added drop-wise to the reaction mixture, which was stirred briefly in the ice bath, and then allowed to warm to 25° C. and stir for 2 hours. The reaction solution of C60 was used directly in the following step.

Conversion of C64 to C65 was carried out using the method described for synthesis of C34 from C33 in Examples 8 and 9. LCMS of intermediate 3-(4-fluorobenzyl)-3,8-diazabicyclo[3.2.1]octane, bis(trifluoroacetic acid) salt: m/z 221.1 [M+H]+. In this case, purification was carried out via silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) to afford C65 as a colorless gum. Yield: 150 mg, 0.302 mmol, 88% over 2 steps. LCMS m/z 497.2 [M+H]+.

Methylamine (2 M solution in tetrahydrofuran; 0.245 mL, 0.490 mmol) was added to a solution of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (95 mg, 0.44 mmol) in ethanol (2 mL) and the reaction mixture was heated to 80° C. for 20 hours. Concentration in vacuo provided the product as an oil (105 mg); this material was used in the following step without additional purification.

A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (30.2 mg, 0.15 mmol) in N,N-dimethylformamide (0.5 mL) was added to 1-chloroisoquinoline (24.5 mg, 0.15 mmol) in a reaction vial. Potassium tert-butoxide (1 M solution in tetrahydrofuran; 0.45 mL, 0.45 mmol) was added, and the reaction mixture was shaken at 60° C. for 18 hours, then at 100° C. for 1 hour. It was then partitioned between half-saturated aqueous sodium bicarbonate solution (1.5 mL) and ethyl acetate (2.4 mL) and subjected to vortexing, followed by centrifugation to break up an emulsion. The organic layer was eluted through a solid phase extraction cartridge (6 mL) charged with sodium sulfate (˜1 g); this extraction procedure was repeated twice, and the combined eluents were concentrated in vacuo. A mixture of trifluoroacetic acid and 1,2-dichloroethane (1:1, 1 mL) was added, and the reaction mixture was shaken at room temperature for 2.5 hours, whereupon it was concentrated in vacuo and dissolved in 1,2-dichloroethane (2.4 mL) with vortexing. This material was loaded onto an SCX (strong cation exchanger) solid phase extraction cartridge (Silicycle, 6 mL, 1 g); the vial was rinsed with a mixture of methanol and 1,2-dichloroethane (1:1; 2×2.4 mL). The cartridge was eluted with methanol (5 mL), followed by a solution of triethylamine in methanol (1 M, 7.5 mL) to elute the deprotected intermediate. Fractions containing the desired material were concentrated in vacuo, and the residue was azeotroped with toluene (2×1 mL) to remove trace methanol. The residue was dissolved in dichloromethane (0.5 mL).

MCYP-P1.2-B12 (Codexis; 6.8 mg, 0.72 nmol/mg) was treated with the buffer solution prepared above (27.4 mL), followed by the solution of 6 prepared above. The reaction mixture was divided in half (14.2 mL each) and transferred into two 25 mL glass vials; the reaction mixtures were left open to the atmosphere and shaken on an orbital shaker (30° C., 225 rpm) for 24 hours. The combined reaction mixtures contained:

A solution of C86 (2.0 grams, 2.7 mmol) in tetrahydrofuran (26 mL) was added to 5% palladium on carbon (Evonik Noblyst P1142; 40 mg) in a Biotage Atlantis reactor. Additional tetrahydrofuran (4.0 mL) was used to rinse the vessel containing starting material; this was added to the reaction mixture. The reactor was purged three times with nitrogen while the reaction mixture was stirred, and then three times with hydrogen without stirring. The hydrogen pressure was brought to 5 psig at 25° C., and then to 15 psig. The agitation was increased to 1200 rpm for 4 hours, whereupon the reactor was purged three times with nitrogen, and the reaction mixture was filtered. The filter cake was rinsed with tetrahydrofuran (20 mL), the combined filtrates were concentrated in vacuo, and the residue was dissolved in tert-butyl methyl ether (300 mL) and concentrated again. This dissolution/concentration was repeated, affording the product as a white foam. Yield: 1.35 g, 2.45 mmol, 91%.

1. 3,3,3-Trifluoropropane-1,2-diol was converted to 3-{[tert-butyl(dimethyl)silyl]oxy}-1,1,1-trifluoropropan-2-ol using the method described for synthesis of C59 from C58 in Examples 19, 20 and 21. 2. Reaction of 4-[4-(piperidin-4-yl)pyrimidin-2-yl]morpholine, hydrochloride salt with bis(trichloromethyl) carbonate and 3-{[tert-butyl(dimethyl)silyl]oxy}-1,1,1-trifluoropropan-2-ol (see footnote 1) in the presence of N,N-diisopropylethylamine afforded 3-{[tert-butyl(dimethyl)silyl]oxy}-1,1,1-trifluoropropan-2-yl 4-[2-(morpholin-4-yl)pyrimidin-4-yl]piperidine-1-carboxylate. This material was desilylated via treatment with acetic acid in a mixture of water and tetrahydrofuran to afford Example 35. 3. Examination of coupling constants in the NMR spectra of rel-(2S,3R)-1,1,1,4,4,4-hexafluorobutane-2,3-diol and rel-(2R,3R)-1,1,1,4,4,4-hexafluorobutane-2,3-diol allowed tentative assignment of the starting material used for Example 36 as the rel-(2S,3R) isomer. 4. Reaction of C19 with bis(trichloromethyl) carbonate and rel-(2S,3R)-1,1,1,4,4,4-hexafluorobutane-2,3-diol in the presence of N,N-diisopropylethylamine afforded Example 36. 5. Alkylation of C6 with 2-(chloromethyl)pyridine in the presence of potassium hydroxide in acetone provided the requisite tert-butyl (1α,5α,6α)-6-[1-(pyridin-2-ylmethyl)-1H-pyrazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate. 6. Reaction of C13 with tetrahydro-2H-pyran-4-yl methanesulfonate in the presence of cesium carbonate and potassium iodide, at elevated temperature in N,N-dimethylformamide, provided the requisite tert-butyl 4-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl]piperidine-1-carboxylate. 7. The carbonate reagent employed in this case was 1-({[(3-{[tert-butyl(dimethyl)silyl]oxy}-1,1,1-trifluoropropan-2-yl)oxy]carbonyl}oxy)pyrrolidine-2,5-dione, prepared from 3-{[tert-butyl(dimethyl)silyl]oxy}-1,1,1-trifluoropropan-2-ol (see footnote 1) using the general method described for synthesis of C17 in Example 3. 8. tert-Butyl 2,9-diazaspiro[5.5]undecane-2-carboxylate was converted to 2-tert-butyl 9-{(2R)-1,1,1-trifluoro-3-[(4-methoxybenzyl)oxy]propan-2-yl}2,9-diazaspiro[5.5]undecane-2,9-dicarboxylate using the method described for synthesis of C29 in Example 6. Treatment with trifluoroacetic acid removed both protecting groups, affording (2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl 2,9-diazaspiro[5.5]undecane-9-carboxylate, which was then subjected to reductive amination with 4-fluorobenzaldehyde and sodium triacetoxyborohydride to afford Example 41. 9. Reaction of C23 with 4-fluorobenzaldehyde in the presence of 1H-benzotriazole and acetic acid provided the corresponding imine; in situ treatment with methylmagnesium bromide then afforded the requisite tert-butyl 4-[1-(4-fluorophenyl)ethyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate. Example 43 is a diastereomeric mixture, with both stereochemistries present at the methyl group. 10. Separation of Example 43 into its component diastereomers was effected via supercritical fluid chromatography [Column: Chiral Technologies Chiralpak AD, 5 μm; Mobile phase: 4:1 carbon dioxide: (0.1% ammonium hydroxide in ethanol)]. The first-eluting diastereomer was Example 44, and the second-eluting diastereomer was Example 45. 11. In this case, tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate was reacted with tetrahydro-2H-pyran-4-amine, and the resulting tert-butyl 4-hydroxy-4-[(tetrahydro-2H-pyran-4-ylamino)methyl]piperidine-1-carboxylate was N-alkylated with 1-(bromomethyl)-4-fluorobenzene in the presence of potassium carbonate; this afforded the requisite tert-butyl 4-{[(4-fluorobenzyl)(tetrahydro-2H-pyran-4-yl)amino]methyl}-4-hydroxypiperidine-1-carboxylate. 12. tert-Butyl 4-[(tetrahydro-2H-pyran-4-ylamino)methyl]piperidine-1-carboxylate was synthesized via reductive amination of tetrahydro-4H-pyran-4-one with tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, using magnesium sulfate and silica gel followed by sodium triacetoxyborohydride. 13. Conditions for analytical HPLC. Column: Waters Atlantis dC18, 4.6×50 mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 5.0% to 95% B, linear over 4.0 minutes; Flow rate: 2 mL/minute. 14. Intermediate tert-butyl 4-({[(4-fluorophenyl)sulfonyl]amino}methyl)piperidine-1-carboxylate was reacted with iodomethane and potassium carbonate to provide tert-butyl 4-({[(4-fluorophenyl)sulfonyl](methyl)amino}methyl)piperidine-1-carboxylate. 15. The requisite 2-chloro-4-(1-methyl-1H-pyrazol-5-yl)pyridine was prepared via a Suzuki reaction between 2-chloro-4-iodopyridine and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, mediated via [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(I). 16. Suzuki reaction of 2-bromo-6-chloropyridine and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, mediated via [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), afforded 2-chloro-6-(1-methyl-1H-pyrazol-5-yl)pyridine. 17. The requisite sulfonic acid was prepared from the corresponding bromo compound via reaction with a mixture of potassium disulfite, palladium(II) acetate, triphenylphosphine, tetraethylammonium bromide, sodium formate and 1,10-phenanthroline in N,N-dimethylformamide at elevated temperature. The sulfonic acid was cooled to 0° C., treated with C31 and N-chlorosuccinimide, and stirred at 30° C. for 1 hour. The resulting sulfonamide was deprotected via treatment with trifluoroacetic acid in dichloromethane to provide the product of the Example. 18. Conditions for analytical HPLC. Column: Waters XBridge C18, 2.1×50 mm, 5 μm; Mobile phase A: 0.0375% trifluoroacetic acid in water; Mobile phase B: 0.01875% trifluoroacetic acid in acetonitrile; Gradient: 10% to 100% B over 4.0 minutes; Flow rate: 0.8 mL/minute. 19. N-Benzyl-2-oxo-1,3-oxazolidine-3-sulfonamide was used as the sulfonylating reagent in this case, in a mixture of triethylamine and acetonitrile. 20. Reaction of C31 and 4-bromobenzenesulfonyl chloride provided (2R)-1,1,1-trifluoro-3-[(4-methoxybenzyl)oxy]propan-2-yl 4-[(4-bromophenyl)sulfonyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate, which was then converted to (2R)-1,1,1-trifluoro-3-[(4-methoxybenzyl)oxy]propan-2-yl 4-({4-[(trimethylsilyl)ethynyl]phenyl}sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate by reaction with ethynyl(trimethyl)silane, copper(I) iodide, and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Desilylation was effected via treatment with potassium carbonate and methanol to afford (2R)-1,1,1-trifluoro-3-[(4-methoxybenzyl)oxy]propan-2-yl 4-[(4-ethynylphenyl)sulfonyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate; final deprotection using trifluoroacetic acid provided Example 68. 21. Reaction of tert-butyl 4-oxopiperidine-1-carboxylate with nitroethane and triethylamine provided tert-butyl 4-hydroxy-4-(1-nitroethyl)piperidine-1-carboxylate, which was hydrogenated to afford tert-butyl 4-(1-aminoethyl)-4-hydroxypiperidine-1-carboxylate. This material was treated with 4-fluorobenzenesulfonyl chloride and potassium carbonate, followed by 1,2-dibromoethane, to provide the requisite intermediate tert-butyl 4-[(4-fluorophenyl)sulfonyl]-5-methyl-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate. 22. Separation to provide the diastereomers of Examples 70 and 71 was effected via supercritical fluid chromatography [Column: Chiral Technologies Chiralpak AD, 5 μm; Mobile phase A: carbon dioxide; Mobile phase B: 2-propanol; Gradient: 25% to 100% B). The first-eluting diastereomer was Example 70, and the second-eluting diastereomer was Example 71. 23. tert-Butyl 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate was treated with sodium hydride and 1-(chloromethyl)-4-fluorobenzene to afford tert-butyl 3-(4-fluorobenzyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate; deprotection with hydrogen chloride in 1,4-dioxane provided the requisite 3-(4-fluorobenzyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one. 24. In this case, the final deprotection was effected with hydrogen chloride in 1,4-dioxane, rather than trifluoroacetic acid. 25. Compound C31 was allowed to react with the appropriate sulfonyl chloride and triethylamine; the resulting sulfonamide was deprotected with trifluoroacetic acid in dichloromethane to afford the product of the Example. 26. Conditions for analytical HPLC. Column: Waters XBridge C18, 2.1×50 mm, 5 μm; Mobile phase A: 0.0375% trifluoroacetic acid in water; Mobile phase B: 0.01875% trifluoroacetic acid in acetonitrile; Gradient: 1% to 5% B over 0.6 minutes; 5% to 100% B over 3.4 minutes; Flow rate: 0.8 mL/minute. 27. 2-Bromoethanol was slowly added to a solution of chlorosulfonyl isocyanate in dichloromethane at 0° C. After an hour, a mixture of 1-(pyridin-2-yl)methanamine and triethylamine was slowly added to the 0° C. reaction mixture. Removal of solvent provided 2-oxo-N-(pyridin-2-ylmethyl)-1,3-oxazolidine-3-sulfonamide, which was used as the sulfonylating reagent in this case, in a mixture of triethylamine and acetonitrile. 28. The requisite tert-butyl 4-[1-(4-ethynylphenyl)-1H-pyrazol-3-yl]piperidine-1-carboxylate was prepared as follows: tert-butyl 4-acetylpiperidine-1-carboxylate was converted to tert-butyl 4-[1-(4-bromophenyl)-1H-pyrazol-3-yl]piperidine-1-carboxylate using the methods described for synthesis of C18 from C4 that are found in Examples 1 and 3. Reaction with ethynyl(trimethyl)silane, copper(I) iodide and tetrakis(triphenylphosphine)palladium(0), followed by removal of the silyl group via treatment with potassium carbonate in methanol, provided tert-butyl 4-[1-(4-ethynylphenyl)-1H-pyrazol-3-yl]piperidine-1-carboxylate. 29. In this case, the enantiomer of C1 was employed; this may be prepared similarly, via the use of (2S)-2-(trifluoromethyl)oxirane rather than (2R)-2-(trifluoromethyl)oxirane. 30. A 0° C. solution of 6 in acetonitrile was treated with 5 equivalents of diphosphoryl tetrachloride; after one to two hours at 0° C., the appropriate alcohol (40 equivalents) was added, generating a mixture of the mono- and di-alkyl phosphate esters. 31. Reversed phase HPLC was used to separate the monomethyl and dimethyl phosphate esters. Column: Phenomenex Gemini NX C18, 5 μm; Mobile phase A: 0.1% ammonium hydroxide in water; Mobile phase B: 0.1% ammonium hydroxide in acetonitrile; Gradient: 50% to 100% B. The first-eluting product was Example 85, and the second-eluting product was Example 86. 32. Reversed phase HPLC was used to separate the monoethyl and diethyl phosphate esters. Column: Phenomenex Gemini NX C18, 5 μm; Mobile phase A: 0.1% ammonium hydroxide in water; Mobile phase B: 0.1% ammonium hydroxide in acetonitrile; Gradient: 50% to 100% B. The first-eluting product was Example 87, and the second-eluting product was Example 88. 33. In this case, 2-(dimethylamino)ethanol was used in place of methanol. The product was purified using reversed phase HPLC (Column: Phenomenex Luna C18, 5 μm; Mobile phase A: 0.1% formic acid in water; Mobile phase B: 0.1% formic acid in acetonitrile; Gradient: 50% to 100% B). 34. In this case, 2-hydroxy-N,N,N-trimethylethanaminium chloride was used in place of methanol.

A pH 8.0 buffer solution was prepared, containing 0.1 M aqueous potassium phosphate and 2 mM magnesium chloride. A stock solution of substrate was prepared as follows: tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (18.0 g, 70.5 mmol) was dissolved in water containing 4% dimethyl sulfoxide (14.4 mL). Warming and stirring were required for dissolution, and the resulting solution was maintained at 40° C. Propan-2-amine, hydrochloride salt (16.8 g, 176 mmol) was added to a mixture of pyridoxal 5′-phosphate monohydrate (1.87 g, 7.05 mmol) and the pH 8.0 buffer (300 mL). The resulting pH was approximately 6.5; the pH was adjusted to 8 via addition of aqueous potassium hydroxide solution (6 M; approximately 4 mL). The stock solution of substrate was added via syringe, in 5 mL portions, resulting in a suspension, still at pH 8. Codex® ATA-200 transaminase (batch #11099; 1.4 g) was almost completely dissolved in pH 8 buffer (20 mL), and poured into the reaction mixture. Additional pH 8 buffer (25.6 mL) was used to ensure complete transfer of the enzyme. The reaction mixture was stirred at 35° C. with a nitrogen sweep (32 mL/minute) through a needle placed approximately 0.5 cm above the reaction surface. Due to difficulties in stirring, vacuum (220 Torr, 300 mbar) was applied after 3 hours, to remove the acetone generated by the transamination reaction. The suspended solids were broken up manually, which improved the stirring of the reaction mixture. After 26 hours, the reaction mixture was allowed to cool to room temperature, and aqueous hydrochloric acid (6 M, 5 mL) was added, to bring the pH from 8 to 6.5. After addition of ethyl acetate (200 mL), the mixture was vigorously stirred for 5 minutes and then filtered through diatomaceous earth (43 g; this filter aid had been slurried in water prior to being introduced into the filter funnel. The water was then removed, providing a tightly packed bed). The filter pad was washed sequentially with water (120 mL) and ethyl acetate (100 mL), and the aqueous layer of the combined filtrates was adjusted to pH 9-9.5 with aqueous potassium hydroxide solution (6 M; approximately 10 mL). The aqueous layer was then treated with dichloromethane (200 mL), and the resulting mixture was vigorously stirred for 5 minutes before being filtered through a pad of diatomaceous earth. The filter pad was washed with dichloromethane (100 mL), and the aqueous layer of the combined filtrates was extracted twice with dichloromethane, in the same manner as that described above, with adjustment of the pH to 9-10 (this required approximately 2 mL of the 6 M aqueous potassium hydroxide solution in both cases). All of the dichloromethane extracts were combined and dried over sodium sulfate with vigorous stirring. Filtration and concentration in vacuo afforded the product as an oily yellow solid (14.76 g). A fourth extraction was carried out in the same manner, but in this case the aqueous layer was adjusted to a pH of >10. The product obtained from this extraction was a white solid (1.9 g). Combined yield: 16.61 g, 64.79 mmol, 92%. 1H NMR (500 MHz, CDCl3) δ 3.95 (dd, J=9.0, 5.6 Hz, 1H), 3.69-3.63 (m, 1H), 3.62-3.52 (m, 3H), 3.38-3.27 (m, 2H), 2.6-2.2 (v br s, 2H), 2.07 (dd, J=13.0, 7.6 Hz, 1H), 1.78-1.71 (m, 1H), 1.69-1.56 (m, 2H), 1.55-1.47 (m, 2H), 1.45 (s, 9H).

A small sample of C94 was derivatized via reaction with benzenesulfonyl chloride and saturated aqueous sodium bicarbonate solution for 1 hour at 40° C. The reaction mixture was extracted with ethyl acetate, and the solvent was removed from the extract under a stream of nitrogen. Supercritical fluid chromatographic analysis (Column: Chiral Technologies Chiralcel OJ-H, 5 μm; Mobile phase A: carbon dioxide; Mobile phase B: methanol; Gradient: 5% to 60% B) revealed the product to have an enantiomeric excess of >99%. Injection under the same conditions of samples of C48 and C49 established the derivatization product as identical to C48, the absolute configuration of which was determined via X-ray crystallographic analysis (see above).

Conversion of C96 to the product was carried out using the method described for synthesis of C89 from C88 in Example 92. The product was obtained as a colorless gum. Yield: 67 mg, 0.12 mmol, 57%. LCMS m/z 573.0 [M+Na+].

Trifluoroacetic acid (0.6 mL) was added drop-wise to a solution of C101 (70.0 mg, 0.220 mmol) in dichloromethane (2 mL), and the reaction mixture was stirred at 25° C. for 2 hours. Volatiles were removed under reduced pressure to provide 3-phenyl-1-oxa-8-azaspiro[4.5]decane, trifluoroacetate salt, as a yellow gum. This material was dissolved in acetonitrile (2 mL), cooled to 0° C., and slowly treated with triethylamine (89.5 mg, 0.884 mmol). After this solution had stirred for 30 minutes, C2 (reaction solution in acetonitrile containing 0.221 mmol) was added at 0° C. The reaction mixture was stirred at 25° C. for 18 hours, whereupon it was concentrated in vacuo and purified by preparative thin layer chromatography on silica gel (Eluent: 3:1 petroleum ether/ethyl acetate), affording the product as a yellow gum (120 mg). This material was taken directly to the following step. LCMS m/z 516.1 [M+Na+].

Trifluoroacetic acid (2 mL) was added to a 0° C. suspension of C100 (65 mg, 0.20 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at 18° C. for 2 hours, whereupon it was concentrated in vacuo to provide the deprotected material as a yellow gum. The gum was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with C2 (reaction solution in acetonitrile containing 0.24 mmol) and triethylamine (166 mg, 1.64 mmol). This reaction mixture was stirred at 18° C. for 16 hours, and then treated with additional C2 (reaction solution in acetonitrile containing 0.24 mmol). Stirring was continued at 18° C. for an additional 16 hours. Volatiles were removed under reduced pressure, and the residue was subjected to chromatography on silica gel (Gradient: 0% to 100% ethyl acetate in petroleum ether) to afford the product as a yellow gum (101 mg). This material was used in the following step without additional purification. LCMS m/z 516.1 [M+Na+]

Conversion of C108 to the product was carried out using the method described for synthesis of C89 from C88 in Example 92. The product was obtained as a colorless gum. Yield: 500 mg, 0.93 mmol, quantitative. LCMS m/z 539.1 [M+H]+.

A solution of tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (36 mg, 0.15 mmol) in pyridine (0.4 mL) was added to a solution of benzenesulfonyl chloride (39.7 mg, 0.225 mmol) and N,N-dimethylpyridin-4-amine (0.25 mg, 2.0 μmol) in pyridine (0.4 mL), and the reaction mixture was shaken at room temperature for 2 days. The pyridine was removed in vacuo, and the residue was partitioned between half-saturated aqueous sodium bicarbonate solution (1.5 mL) and ethyl acetate (2.4 mL). After the mixture had been vortexed, the organic layer was eluted through a solid phase extraction cartridge (6 mL) charged with sodium sulfate (1 g); this extraction procedure was repeated twice, and the combined eluents were concentrated in vacuo. The residue was treated with a mixture of 1,2-dichloroethane and trifluoroacetic acid (1:1; 1 mL), shaken at room temperature for 2.5 hours, and concentrated under reduced pressure. The remaining material was dissolved in 1,2-dichloroethane (2.4 mL), vortexed, and loaded onto an SCX (strong cation exchanger) solid phase extraction cartridge (Silicycle, 6 mL, 1 g); the vial was rinsed with a mixture of methanol and 1,2-dichloroethane (1:1; 2×2.4 mL). The cartridge was eluted with methanol (5 mL), followed by a solution of triethylamine in methanol (1 M, 7.5 mL) to elute the deprotected intermediate. Fractions containing the desired material were concentrated in vacuo, and the residue was azeotroped with toluene (2×1 mL) to remove trace methanol. The resulting material was dissolved in dichloromethane (0.5 mL).

Trifluoroacetic acid (20 mL) was added to a solution of C122 (from the previous step; 16 g, ≤38.8 mmol) in dichloromethane (100 mL), and the reaction mixture was stirred at 15° C. for 2 hours. Removal of volatiles in vacuo afforded the product as a brown gum (20 g). This material was used directly in the following step. LCMS m/z 255.2 [M+H]+.

Assessment of MAGL inhibition utilizes human recombinant Monoacylglycerol Lipase and the fluorogenic substrate 7-hydroxycoumarinyl arachidonate (7-HCA, Biomol ST-502). 400 nL of a test compound at decreasing concentration (ranging from 150 μM down to 1.5 nM) was spotted into a 384-well back plate (PerkinElmer, 6007279) using a Labcyte Echo, followed by addition of 10 μL of MAGL enzyme in assay buffer (50 mM HEPES, pH 7.4, 100 mM NaCl, 5 mM MgCl2, 0.1% Triton X-100 and 25% glycerin). An equal volume of 7-HCA in assay buffer with 10% DMSO was added either immediately (T=0 min) or after a 30 minute incubation (T=30 min) to initiate the reaction. The final concentration of MAGL enzyme was 88 μM and 7-HCA substrate was 5 μM. After these dilutions, the final concentration of the test compound ranged from 3 μM to 0.03 nM. The reaction was allowed to progress for 60 minutes, after which the plate was read at an Ex/Em of 340/465. Percent inhibitions were calculated based on control wells containing no compound (0% inhibition) and a control compound (e.g., a MAGL inhibitor whose activity is known or was previously reported in the literature, such as one with about 100% inhibition). IC50 values were generated based on a four parameter fit model using ABASE software from IDBS. See e.g., Wang, Y. et al., “A Fluorescence-Based Assay for Monoacylglycerol Lipase Compatible with Inhibitor Screening,” Assay and Drug Development Technologies, 2008, Vol. 6 (3) pp 387-393 (reporting an assay for measuring MAGL activity).

To measure MAGL inactivation, the same protocol for the (T=0 min) MAGL inhibition IC50 assay was performed with data collected every minute to acquire enzyme progress curves at decreasing concentrations of compound. Kobs values were calculated from this data and kinact/KI ratios were determined from a plot of Kobs values vs. compound concentrations.

Assessment of FAAH inhibition utilizes human recombinant FAAH and the fluorescent substrate, Arachidonoyl-AMC. 400 nL of a test compound at decreasing concentrations was spotted into a 384-well back plate (PerkinElmer, 6007279) using a Labcyte Echo, followed by addition of 10 μl of FAAH enzyme (Cayman 10010183) in assay buffer (50 mM Tris, pH 9.0, 1 mM EDTA). After a 30 minute incubation at room temperature, 10 μL of Arachidonyl-AMCA was added in assay buffer with 16% DMSO. Final concentration of FAAH enzyme was 0.0125 Units and AAMCA substrate was used at the Km of 5 μM. After these dilutions, the final concentration of the test compound ranged from 3 μM to 0.03 nM. The reaction was allowed to progress for 60 minutes, after which the plate was read on a Molecular Devices FlexStation reader at an Ex/Em of 355/460. Percent inhibitions were calculated based on controls wells containing either no compound (0% inhibition) or a control compound (e.g., an FAAH inhibitor whose activity is known or was previously reported in the literature, such as one with about 100% inhibition). IC50 values were generated based on a four parameter fit model using ABASE software from IDBS.

Blood samples were taken at various times after administration and submitted to analysis for the parent compound (Examples 9 or 6) and prodrug compound (Examples 31 or 32, respectively) using an LC-MS-MS assay. Pharmacokinetic parameters derived from the plasma analytical data were determined using Watson LIMS 7.2.003 (Thermo Fisher Scientific, Waltham, Mass.). The results are given in Tables BB-2 to BB-5.

Blood samples were taken at various times after administration and submitted to analysis for the parent compound (Example 9 or 6) and its prodrug compound (Example 31 or 32, respectively) using an LC-MS-MS assay. Pharmacokinetic parameters derived from the plasma analytical data were determined using Watson LIMS 7.2.003 (Thermo Fisher Scientific, Waltham, Mass.). The results are given in Tables BB-7 to BB-10.

Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appendant claims. Each reference (including all patents, patent applications, journal articles, books, and any other publications) cited in the present application is hereby incorporated by reference in its entirety.

Claims

1. A compound of Formula I-a or I-a1:

or a pharmaceutically acceptable salt thereof, wherein: the moiety of “N(R1)(R2)” is a moiety of Formula a-26:

ring A2 is 5- or 6-membered cycloalkyl or heterocycloalkyl; t2 is 0, 1, 2, or 3; t3 is 0, 1, 2, or 3; each of R5 and R6 is independently H or C1-4 alkyl; R7 is H, C1-6 alkyl, C3-7 cycloalkyl, or R10, wherein the C1-6 alkyl of R7 is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C1-4 alkoxy, C1-4 haloalkoxy, and C3-6 cycloalkyl, and wherein the C3-7 cycloalkyl of R7 is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; R8 is L1-R11, -L2-R12, -L3-R13, -L4-R14, —C(R15)(Cy1)(Cy2), —C(R15)(Cy1)[—NR23—S(═O)2-Cy2], or -L5-N(-L6-Cy3)(-L7-Cy4); each R9 is independently OH, oxo, halogen, optionally substituted C1-4 alkyl, optionally substituted C1-4 alkoxy, or optionally substituted C3-6 cycloalkyl; R10 is —P(═O)(OR81)(OR82) or —S(═O)2OR90; each of L1, L2, L3, and L4 is independently absent, —(CR21R22)m, —NR23—, —O—, —C(═O)—, —S(═O)2—, —S(═O)2—(CR21R22)n—, —C(═O)—(CR21R22)n—, —S(═O)2—NR23—, —C(═O)—NR23—, —(CR21R22)f1— NR23—(CR21R22)f2—, —(CR21R22)f1—O—(CR21R22)f2—, —C(═O)—NR23—(CR21R22)p—, or —S(═O)2—NR23—(CR21R22)p—; L5 is absent or —(CR21R22)—; L6 is absent or —(CR21R22)—; L7 is absent, —(CR21R22)—, or —S(═O)2—; R11 is 5- to 10-membered heteroaryl optionally substituted with one or more independently selected R31; R12 is 4- to 14-membered heterocycloalkyl optionally substituted with one or more independently selected R32; R13 is C6-10 aryl optionally substituted with one or more independently selected R33; R14 is C3-14 cycloalkyl optionally substituted with one or more independently selected R34; R15 is H, OH, halogen, C1-4 alkoxy, C1-4 alkyl, or cyclopropyl; each of R21 and R22 is independently H, OH, halogen, C1-3 alkyl, or cyclopropyl, wherein the C1-3 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C1-3 alkoxy, C1-3 haloalkoxy, and cyclopropyl; R23 is H, C1-4 alkyl, or cyclopropyl; each of R31, R32, R33, and R34 is independently selected from the group consisting of halogen, —N(Ra)(Rb), —N(Rc)(C(═O)Rd), —N(Rc)(S(═O)2Rd), —C(═O)—N(Ra)(Rb), —C(═O)—Rd, —C(═O)—ORd, —OC(═O)—Rd, —N(Rc)(S(═O)2Rd), —S(═O)2—N(Ra)(Rb), —SRd, —S(═O)2Rd, —ORd, —OR35, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, (C3-10 cycloalkyl)-C1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (5- to 10-membered heteroaryl)-C1-4 alkyl-, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, (C3-10 cycloalkyl)-C1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (5- to 10-membered heteroaryl)-C1-4 alkyl- is optionally substituted with one or more independently selected R36; and wherein each of the C1-6 alkyl, C3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, (C3-10 cycloalkyl)-C1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (5- to 10-membered heteroaryl)-C1-4 alkyl- is further optionally substituted one or more oxo; each R35 is independently selected from the group consisting of H, C1-6 alkyl, C3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, (C3-10 cycloalkyl)-C1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (5- to 10-membered heteroaryl)-C1-4 alkyl-, wherein each of the C1-6 alkyl, C3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, (C3-10 cycloalkyl)-C1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (5- to 10-membered heteroaryl)-C1-4 alkyl- is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —C(═O)C1-4 alkyl, —C(═O)OH, —C(═O)O—C1-4 alkyl, —C(═O)NHC1-4 alkyl, —C(═O)N(C1-4 alkyl)2, oxo, —OH, —OC(═O)—C1-4 alkyl, —OC(═O)O—C1-4 alkyl, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, —NHC(═O)C1-4 alkyl, —NHC(═O)OC1-4 alkyl, —NHC(═O)NHC1-4 alkyl, and C1-4 alkoxy; each R36 is independently selected from the group consisting of halogen, —OH, —NO2, —CN, —SF5, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, —N(Ra)(Rb), —N(Rc)(C(═O)Rd), —C(═O)—N(Ra)(Rb), —C(═O)—Rd, —C(═O)—ORd, —OC(═O)—Rd, —N(Rc)(S(═O)2Rd), —S(═O)2—N(Ra)(Rb), —SRd, —S(═O)2Rd, and —ORd, wherein each of the C1-6 alkyl, C3-7 cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, —OH, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, —N(Ra)(Rb), —N(Rc)(C(═O)Rd), —C(═O)—ORd, —C(═O)H, —C(═O)Rd, —C(═O)N(Ra)(Rb), —N(Rc)(S(═O)2Rd), —S(═O)2—N(Ra)(Rb), —SRd, —S(═O)2Rd, and —ORd; each of R81, R82, and R90 is independently selected from the group consisting of H, C1-6 alkyl, C3-7 cycloalkyl, and (C3-7 cycloalkyl)-C1-4 alkyl-, wherein each of the C1-6 alkyl, C3-7 cycloalkyl, and (C3-7 cycloalkyl)-C1-4 alkyl- is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, —OH, oxo, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl; or OR81 and OR82, together with the P(═O) to which they are attached, form 4- to 10-membered heterocycloalkyl that is further optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, —OH, oxo, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, and C3-6 cycloalkyl; each of Cy1, Cy2, Cy3, and Cy4 is independently selected from the group consisting of R11, R12, R13, and R14; each Ra is independently H, C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, or (C3-7 cycloalkyl)-C1-4 alkyl-; each Rb is independently H or selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, C6-10 aryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-C1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (5- to 10-membered heteroaryl)-C1-4 alkyl-, wherein each of the selections from the group is optionally substituted with one or more substituents each independently selected from the group consisting of —OH, —CN, C1-4 alkyl, C3-7 cycloalkyl, C1-4 hydroxylalkyl, —S—C1-4 alkyl, —C(═O)H, —C(═O)—C1-4 alkyl, —C(═O)—O—C1-4 alkyl, —C(═O)—NH2, —C(═O)—N(C1-4 alkyl)2, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or Ra and Rb, together with the N atom to which they are attached, form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —OH, oxo, —C(═O)H, —C(═O)OH, —C(═O)—C1-4 alkyl, —C(═O)—NH2, —C(═O)—N(C1-4 alkyl)2, —CN, C1-4 alkyl, C3-6 cycloalkyl, (C3-6 cycloalkyl)-C1-2 alkyl-, C1-4 alkoxy, C1-4 hydroxylalkyl, C1-4 haloalkyl, and C1-4 haloalkoxy; each Rc is independently selected from the group consisting of H, C1-4 alkyl, C3-7 cycloalkyl, and (C3-7 cycloalkyl)-C1-4 alkyl-; each Rd is independently selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, a 4- to 14-membered heterocycloalkyl, C6-10 aryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-C1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (5- to 10-membered heteroaryl)-C1-4 alkyl-, wherein each of the selections from the group is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CF3, —CN, —OH, oxo, —S—C1-4 alkyl, C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each of f1 and f2 is independently 0, 1, or 2, provided that the sum of f1 and f2 is 1, 2, or 3; m is 1, 2, or 3; n is 1, 2, or 3; and p is 1, or 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of I-a1.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the moiety of Formula a-26 is a moiety of Formula a-36:

wherein ring A3 is 5- or 6-membered heterocycloalkyl and wherein the O atom shown in the ring is linked directly to the carbon bridge-head.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-1:

wherein each R9b is independently F, Cl, methyl, or C1 fluoroalkyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the moiety of “—N(R1)(R2)” is a moiety of Formula a-46-2:

wherein each R9b is independently F, Cl, methyl, or C1 fluoroalkyl.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of R5 and R6 is independently H or methyl.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of R5 and R6 is H.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is H or R10; and R10 is —P(═O)(OR81)(OR82).

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is H.

10. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein:

R11 is 5- to 6-membered heteroaryl optionally substituted with one or more independently selected R31;

R12 is 5- to 6-membered heterocycloalkyl optionally substituted with one or more independently selected R31;

R13 is phenyl optionally substituted with one or more independently selected R33; and

R14 is C3-8 cycloalkyl optionally substituted with one or more independently selected R34.

11. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R8 is -L1-R11, -L2R12, -L3-R13, or -L4-R14; and each of each of L1, L2, L3, and L4 is —S(═O)2— or —C(═O)—.

12. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R8 is —S(═O)2—R13; R13 is phenyl optionally substituted with one or more independently selected R33; and each R33 is independently selected from the group consisting of halogen, —CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.

13. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein: